Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0016471 vacuolar proton-transporting V-type ATPase complex	IBA GO_REF:0000033	ACCEPT	Summary: Correct core complex annotation. ATP6V0A1 is a subunit of the V0 membrane sector of the vacuolar proton-transporting V-type ATPase complex. Reason: The UniProt record and human V-ATPase structure place ATP6V0A1 in the V0 proton-translocation sector of the assembled V-ATPase complex. Supporting Evidence: file:human/ATP6V0A1/ATP6V0A1-uniprot.txt proton transport subunit a, a ring of proteolipid subunits PMID:33065002 Here, we report cryo-EM structures of a human V-ATPase
GO:0046961 proton-transporting ATPase activity, rotational mechanism	IBA GO_REF:0000033	ACCEPT	Summary: Correct as a contributes_to annotation. ATP6V0A1 is not an isolated catalytic ATPase, but as the V0 a-subunit it contributes to the rotary proton-pumping activity of the complete V-ATPase. Reason: Human V-ATPase is an ATP-driven proton pump; the a-subunit is part of the membrane proton-translocation domain that couples to V1 ATP hydrolysis. Supporting Evidence: PMID:33065002 ATP hydrolysis-driven proton pumps that acidify intracellular vesicles PMID:34909687 responsible for proton translocation
GO:0005886 plasma membrane	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: Supported but not core for ATP6V0A1. V-ATPases can be present at the plasma membrane in specialized contexts, but the main ATP6V0A1 function is organellar acidification. Reason: Keep as a specialized-cell localization rather than a core location for the a1 isoform. Supporting Evidence: file:human/ATP6V0A1/ATP6V0A1-uniprot.txt certain cell types, can be exported to the plasma membrane
GO:0007035 vacuolar acidification	IBA GO_REF:0000033	ACCEPT	Summary: Correct core biological process. ATP6V0A1 contributes to V-ATPase-mediated acidification of intracellular organelles. Reason: Although lysosomal and endosomal terms are more precise in mammalian cells, vacuolar acidification captures the conserved V-ATPase role in organelle lumen acidification. Supporting Evidence: file:human/ATP6V0A1/ATP6V0A1-uniprot.txt acidification of various organelles, such as lysosomes, endosomes PMID:33833240 These data suggested that all ATP6V0A1 missense variants impaired lysosomal acidification in cell lines.
GO:0051117 ATPase binding	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: Supported V0-V1 interface annotation, but non-core. ATP6V0A1 binds V1-sector ATPase subunits as part of V-ATPase assembly/regulation; this interaction is secondary to the proton-pump function. Reason: The ATPase-binding term captures a real subunit-interface property but should not displace the complex-level proton transport function as the core molecular role. Supporting Evidence: PMID:17360703 These interactions represent a novel link between the V(1) and V(0) domains in man
GO:0000220 vacuolar proton-transporting V-type ATPase, V0 domain	IEA GO_REF:0000002	ACCEPT	Summary: Correct V0-domain component annotation from InterPro. ATP6V0A1 is the a-subunit of the V0 membrane sector. Reason: The V0-domain annotation is central to ATP6V0A1 identity and is supported by UniProt and human V-ATPase structural work. Supporting Evidence: file:human/ATP6V0A1/ATP6V0A1-uniprot.txt proton transport subunit a, a ring of proteolipid subunits
GO:0030665 clathrin-coated vesicle membrane	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: Plausible non-core localization. UniProt maps ATP6V0A1 to clathrin-coated vesicle membrane by similarity, consistent with V-ATPase function in vesicular compartments. Reason: This is a specific vesicle-membrane localization, but the core localization/function is broader endolysosomal and synaptic vesicle acidification. Supporting Evidence: file:human/ATP6V0A1/ATP6V0A1-uniprot.txt secretory vesicle, synaptic vesicle
GO:0030672 synaptic vesicle membrane	IEA GO_REF:0000044	ACCEPT	Summary: Correct neuronal vesicle localization. ATP6V0A1 is annotated to synaptic vesicle membrane, and mutant mouse evidence supports a role in synaptic vesicle proton-dependent neurotransmitter loading. Reason: The a1 isoform is brain enriched and supports proton-gradient-dependent synaptic vesicle function. Supporting Evidence: file:human/ATP6V0A1/ATP6V0A1-uniprot.txt secretory vesicle, synaptic vesicle PMID:33833240 the neurotransmitter content of synaptic vesicles was indeed lowered in Atp6v0a1A512P/A512P mice, presumably due to the reduced proton pump activity.
GO:0033179 proton-transporting V-type ATPase, V0 domain	IEA GO_REF:0000002	ACCEPT	Summary: Correct V0-domain component annotation. This is the generic V0-domain term and is already consistent with the PN projection. Reason: ATP6V0A1 is the a-subunit of the V0 proton-translocation sector of V-ATPase. Supporting Evidence: file:human/ATP6V0A1/ATP6V0A1-uniprot.txt proton transport subunit a, a ring of proteolipid subunits
GO:0042470 melanosome	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: Supported but non-core localization. ATP6V0A1 was identified in melanosome fractions, but melanosomes are a specialized lysosome-related organelle context rather than the core role of the gene. Reason: Retain melanosome localization as a specialized organelle location supported by proteomics and UniProt, not as the main ATP6V0A1 function. Supporting Evidence: file:human/ATP6V0A1/ATP6V0A1-uniprot.txt melanosome fractions from stage I to stage IV PMID:12643545 identify protein components of early melanosomes
GO:0046961 proton-transporting ATPase activity, rotational mechanism	IEA GO_REF:0000002	MODIFY	Summary: Correct V-ATPase activity term. ATP6V0A1 contributes to the rotary proton-pumping activity of the complete V-ATPase; the term is appropriate when interpreted in the complex-subunit context already captured by the IBA contributes_to row. Reason: The GO term itself is correct for the V-ATPase complex activity, but the IEA qualifier should be changed from enables to contributes_to because ATP6V0A1 is a V0-sector subunit rather than an isolated catalytic ATPase. Proposed replacements: proton-transporting ATPase activity, rotational mechanism Supporting Evidence: PMID:33065002 ATP hydrolysis-driven proton pumps that acidify intracellular vesicles
GO:1902600 proton transmembrane transport	IEA GO_REF:0000002	ACCEPT	Summary: Correct core process. The V0 a-subunit participates directly in proton transmembrane transport across organelle membranes. Reason: ATP6V0A1 is part of the membrane proton-translocation domain, and pathogenic variants perturb proton translocation/acidification. Supporting Evidence: file:human/ATP6V0A1/ATP6V0A1-uniprot.txt proton transport subunit a, a ring of proteolipid subunits PMID:34909687 responsible for proton translocation
GO:0005515 protein binding	IPI PMID:7896830 Vacuolar H(+)-ATPase mutants transform cells and define a bi...	REMOVE	Summary: Remove. The cited publication defines binding of papillomavirus E5 to the 16 kDa V-ATPase proteolipid subunit, not ATP6V0A1/a1. Reason: This appears to be a mismatched or over-propagated protein-binding annotation. ATP6V0A1 has other valid interaction evidence, but PMID:7896830 does not support ATP6V0A1 protein binding. Supporting Evidence: PMID:7896830 The 16K subunit of the vacuolar H(+)-ATPase binds specifically
GO:0005737 cytoplasm	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Too broad. ATP6V0A1 has cytoplasmic domains but is a multi-pass membrane V-ATPase subunit; cytoplasm alone loses the informative membrane/complex localization. Reason: Prefer membrane-sector and organelle membrane annotations over a broad cytoplasm location. Supporting Evidence: file:human/ATP6V0A1/ATP6V0A1-uniprot.txt Required for assembly and activity of the vacuolar ATPase
GO:0048471 perinuclear region of cytoplasm	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Plausible but non-core transferred localization. Perinuclear cytoplasm is compatible with endolysosomal/Golgi-region organelles but is less informative than the specific membrane compartments. Reason: Keep as broad cellular context from orthology transfer, while relying on lysosomal/endosomal/synaptic vesicle membrane terms for core localization. Supporting Evidence: file:human/ATP6V0A1/ATP6V0A1-uniprot.txt acidification of various organelles, such as lysosomes, endosomes
GO:0097401 synaptic vesicle lumen acidification	IEA GO_REF:0000107	ACCEPT	Summary: Correct neuronal process. ATP6V0A1 supports synaptic vesicle proton gradients needed for neurotransmitter loading. Reason: Mouse variant data show lowered synaptic vesicle neurotransmitter content, consistent with reduced V-ATPase proton-pump activity. Supporting Evidence: PMID:33833240 the neurotransmitter content of synaptic vesicles was indeed lowered in Atp6v0a1A512P/A512P mice, presumably due to the reduced proton pump activity. file:human/ATP6V0A1/ATP6V0A1-uniprot.txt secretory vesicle, synaptic vesicle
GO:0007042 lysosomal lumen acidification	NAS PMID:33065002 Structures of a Complete Human V-ATPase Reveal Mechanisms of...	ACCEPT	Summary: Correct core lysosomal process. Human ATP6V0A1 variants impair lysosomal acidification, and the V-ATPase complex maintains lysosomal pH. Reason: This is one of the strongest ATP6V0A1 process annotations and is directly aligned with the PN lysosomal acidification row. Supporting Evidence: PMID:33065002 pH homeostasis of endosomes and lysosomes PMID:33833240 These data suggested that all ATP6V0A1 missense variants impaired lysosomal acidification in cell lines. PMID:34909687 direct impairment of endolysosome acidification and failure of lysosomal functions.
GO:0016020 membrane	IDA PMID:33065002 Structures of a Complete Human V-ATPase Reveal Mechanisms of...	MARK AS OVER ANNOTATED	Summary: Correct but too broad. ATP6V0A1 is a membrane protein, but generic membrane does not capture its V0-sector/endolysosomal and vesicular membrane identity. Reason: Use specific V-ATPase complex and organelle membrane annotations where possible. Supporting Evidence: file:human/ATP6V0A1/ATP6V0A1-uniprot.txt Required for assembly and activity of the vacuolar ATPase
GO:0033176 proton-transporting V-type ATPase complex	NAS PMID:33065002 Structures of a Complete Human V-ATPase Reveal Mechanisms of...	ACCEPT	Summary: Correct complex annotation. ATP6V0A1 is part of the proton-transporting V-type ATPase complex described structurally in human cells. Reason: The complete human V-ATPase structure and UniProt subunit summary support complex membership. Supporting Evidence: PMID:33065002 Here, we report cryo-EM structures of a human V-ATPase file:human/ATP6V0A1/ATP6V0A1-uniprot.txt proton transport subunit a, a ring of proteolipid subunits
GO:0048388 endosomal lumen acidification	NAS PMID:32001091 Structure and Roles of V-type ATPases.	ACCEPT	Summary: Correct process annotation. V-ATPase acidifies endosomes, and ATP6V0A1 contributes to the proton-translocation sector. Reason: Endosomal acidification is a core organelle-acidification output of V-ATPase. Supporting Evidence: file:human/ATP6V0A1/ATP6V0A1-uniprot.txt acidification of various organelles, such as lysosomes, endosomes PMID:33065002 pH homeostasis of endosomes and lysosomes Reactome:R-HSA-74723 The effect of the proton pump is to allow entry of [H+] ions into the lumen of the endosome.
GO:1902600 proton transmembrane transport	NAS PMID:33065002 Structures of a Complete Human V-ATPase Reveal Mechanisms of...	ACCEPT	Summary: Correct core process. ATP6V0A1 contributes to ATP-driven proton transport across cellular membranes. Reason: This process is supported by V-ATPase structure/function literature and ATP6V0A1 disease variants that impair acidification. Supporting Evidence: PMID:33065002 ATP hydrolysis-driven proton pumps that acidify intracellular vesicles PMID:34909687 responsible for proton translocation
GO:0042470 melanosome	EXP PMID:12643545 Proteomic analysis of early melanosomes: identification of n...	KEEP AS NON CORE	Summary: Supported but non-core localization from melanosome proteomics. Reason: Melanosome localization is experimentally supported, but it is a specialized lysosome-related organelle location rather than the main ATP6V0A1 role. Supporting Evidence: file:human/ATP6V0A1/ATP6V0A1-uniprot.txt melanosome fractions from stage I to stage IV PMID:12643545 identify protein components of early melanosomes
GO:0042470 melanosome	EXP PMID:17081065 Proteomic and bioinformatic characterization of the biogenes...	KEEP AS NON CORE	Summary: Supported but non-core localization from melanosome proteomics across developmental stages. Reason: Retain as specialized lysosome-related organelle localization; do not treat as the core function. Supporting Evidence: file:human/ATP6V0A1/ATP6V0A1-uniprot.txt melanosome fractions from stage I to stage IV PMID:17081065 melanosome proteomes at various developmental stages
GO:0000220 vacuolar proton-transporting V-type ATPase, V0 domain	ISS GO_REF:0000024	ACCEPT	Summary: Correct orthology-supported V0-domain annotation. Reason: The V0-domain role is conserved across V-ATPase a-subunit family members and supported by the human UniProt record. Supporting Evidence: file:human/ATP6V0A1/ATP6V0A1-uniprot.txt proton transport subunit a, a ring of proteolipid subunits file:interpro/panther/PTHR11629/PTHR11629-metadata.yaml VACUOLAR PROTON ATPASES
GO:0005765 lysosomal membrane	TAS PMID:22982048 Lipofuscin is formed independently of macroautophagy and lys...	ACCEPT	Summary: Correct lysosomal membrane localization. Although the original TAS citation is indirect, ATP6V0A1 localization and functional evidence strongly support lysosomal V-ATPase membership. Reason: ATP6V0A1 localizes with lysosomal V-ATPase in cell assays and disease variants impair lysosomal acidification. Supporting Evidence: PMID:33833240 These data suggested that all ATP6V0A1 missense variants impaired lysosomal acidification in cell lines. file:human/ATP6V0A1/ATP6V0A1-uniprot.txt acidification of various organelles, such as lysosomes, endosomes
GO:0005886 plasma membrane	TAS Reactome:R-HSA-6798743	KEEP AS NON CORE	Summary: Supported specialized-cell localization. Reactome places V-ATPase-containing secretory vesicle membranes at the plasma membrane during degranulation. Reason: This is a contextual trafficking/localization annotation and not the primary ATP6V0A1 function. Supporting Evidence: Reactome:R-HSA-6798743 Secretory vesicles provide a reservoir of membrane-associated receptors file:human/ATP6V0A1/ATP6V0A1-uniprot.txt certain cell types, can be exported to the plasma membrane
GO:0005886 plasma membrane	TAS Reactome:R-HSA-6800426	KEEP AS NON CORE	Summary: Supported specialized neutrophil granule/plasma membrane context, but non-core. Reason: Retain as a Reactome-derived specialized localization while keeping organelle acidification as the core role. Supporting Evidence: Reactome:R-HSA-6800426 Ficoli-1 rich granules are a relatively new fourth neutrophil granule population file:human/ATP6V0A1/ATP6V0A1-uniprot.txt certain cell types, can be exported to the plasma membrane
GO:0030667 secretory granule membrane	TAS Reactome:R-HSA-6798743	KEEP AS NON CORE	Summary: Supported secretory granule membrane context for V-ATPase-containing vesicles, but non-core. Reason: Secretory granules are one organelle class acidified by V-ATPase; this is narrower cellular context rather than a separate core function. Supporting Evidence: Reactome:R-HSA-6798743 Secretory vesicles provide a reservoir of membrane-associated receptors file:human/ATP6V0A1/ATP6V0A1-uniprot.txt acidification of various organelles, such as lysosomes, endosomes
GO:0101003 ficolin-1-rich granule membrane	TAS Reactome:R-HSA-6800426	KEEP AS NON CORE	Summary: Supported ficolin-1-rich granule membrane context in neutrophil degranulation, but non-core. Reason: This specific granule class is a specialized immune-cell localization; ATP6V0A1 core function remains V-ATPase proton transport. Supporting Evidence: Reactome:R-HSA-6800426 Ficoli-1 rich granules are a relatively new fourth neutrophil granule population file:human/ATP6V0A1/ATP6V0A1-uniprot.txt acidification of various organelles, such as lysosomes, endosomes
GO:0007035 vacuolar acidification	TAS PMID:22982048 Lipofuscin is formed independently of macroautophagy and lys...	ACCEPT	Summary: Correct organelle acidification process. The original lipofuscin paper is indirect for ATP6V0A1, but independent ATP6V0A1 and V-ATPase evidence strongly supports vacuolar/endolysosomal acidification. Reason: Retain the process because it is supported by direct ATP6V0A1 mutant acidification assays and general V-ATPase structure/function evidence. Supporting Evidence: PMID:33833240 These data suggested that all ATP6V0A1 missense variants impaired lysosomal acidification in cell lines. PMID:33065002 ATP hydrolysis-driven proton pumps that acidify intracellular vesicles
GO:0016241 regulation of macroautophagy	IMP PMID:22982048 Lipofuscin is formed independently of macroautophagy and lys...	KEEP AS NON CORE	Summary: Keep as non-core. V-ATPase dysfunction causes autophagy defects, but this reflects lysosomal/endolysosomal acidification and autophagic flux rather than ATP6V0A1 acting as a dedicated macroautophagy regulator. Reason: Aoto and Bott show autophagy defects when ATP6V0A1/V-ATPase function is impaired; the direct core function is proton pumping and organelle acidification. Supporting Evidence: PMID:33833240 Lysosomal dysfunction resulting in cell death, impaired autophagy, and reduced mTORC1 signaling and synaptic connectivity PMID:22982048 macroautophagy is responsible for the uptake of lipofuscin into the lysosomes. PMID:28024296 localized to the late endosome/lysosome and interacts with the lysosomal v-ATPase to negatively regulate mTORC1 activation
GO:0070062 extracellular exosome	HDA PMID:23533145 In-depth proteomic analyses of exosomes isolated from expres...	MARK AS OVER ANNOTATED	Summary: High-throughput exosome localization, not a core ATP6V0A1 compartment. Reason: Exosome proteomics can reflect vesicular trafficking or membrane protein carryover; it does not define the main site of ATP6V0A1 function. Supporting Evidence: PMID:23533145 exosome preparations were characterized by a shotgun proteomics procedure.
GO:0070062 extracellular exosome	HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos...	MARK AS OVER ANNOTATED	Summary: High-throughput urinary exosome localization, not a core ATP6V0A1 compartment. Reason: Retain the evidence as a high-throughput detection but do not treat extracellular exosome as a primary functional localization. Supporting Evidence: PMID:19056867 Here, we used LC-MS/MS to profile the proteome of human urinary exosomes.
GO:0030670 phagocytic vesicle membrane	TAS Reactome:R-HSA-1222516	KEEP AS NON CORE	Summary: Supported specialized phagocytic vesicle membrane context. V-ATPase acidifies phagosomes, but this is a cell-context-specific location. Reason: Reactome supports V-ATPase-driven phagosomal acidification; the annotation should remain secondary to the general endolysosomal/synaptic vesicle acidification function. Supporting Evidence: Reactome:R-HSA-1222516 ATP hydrolysis drives a 120 degree rotation of the rotor which leads to movement of three protons into the phagosome PMID:33065002 ATP hydrolysis-driven proton pumps that acidify intracellular vesicles
GO:0010008 endosome membrane	TAS Reactome:R-HSA-5252133	ACCEPT	Summary: Correct endosome membrane localization in a V-ATPase assembly/accessory-subunit pathway context. Reason: ATP6V0A1 contributes to V-ATPase complexes on endosomal membranes where proton pumping acidifies the endosomal lumen. Supporting Evidence: PMID:33065002 pH homeostasis of endosomes and lysosomes
GO:0010008 endosome membrane	TAS Reactome:R-HSA-74723	ACCEPT	Summary: Correct endosome membrane localization for endosome acidification. Reason: Endosome membrane is a core V-ATPase location and directly matches endosomal acidification evidence. Supporting Evidence: Reactome:R-HSA-74723 The effect of the proton pump is to allow entry of [H+] ions into the lumen of the endosome. PMID:33065002 pH homeostasis of endosomes and lysosomes
GO:0010008 endosome membrane	TAS Reactome:R-HSA-917841	ACCEPT	Summary: Correct endosome membrane localization in transferrin receptor endosome acidification. Reason: This is a specific Reactome endosomal acidification context for the same core V-ATPase function. Supporting Evidence: Reactome:R-HSA-917841 Acidification of Tf:TfR1 containing endosome PMID:33065002 pH homeostasis of endosomes and lysosomes
GO:0005886 plasma membrane	IDA PMID:17360703 V1 and V0 domains of the human H+-ATPase are linked by an in...	KEEP AS NON CORE	Summary: Supported but non-core plasma membrane localization. The cited interaction work supports V0-V1 linkage, while UniProt treats plasma membrane export as cell-type-specific. Reason: Use as specialized localization context only; organelle membrane acidification remains the primary role. Supporting Evidence: PMID:17360703 These interactions represent a novel link between the V(1) and V(0) domains in man file:human/ATP6V0A1/ATP6V0A1-uniprot.txt certain cell types, can be exported to the plasma membrane
GO:0051117 ATPase binding	IPI PMID:17360703 V1 and V0 domains of the human H+-ATPase are linked by an in...	KEEP AS NON CORE	Summary: Supported V0-V1 interaction with ATP6V1G1/G1, but non-core molecular function. Reason: The G-subunit/a-subunit interaction links V1 and V0 domains and is relevant to assembly/regulation, but proton transport is the core function. Supporting Evidence: PMID:17360703 These interactions represent a novel link between the V(1) and V(0) domains in man
GO:0051117 ATPase binding	IPI PMID:17360703 V1 and V0 domains of the human H+-ATPase are linked by an in...	KEEP AS NON CORE	Summary: Supported V0-V1 interaction with ATP6V1G3/G3, but non-core molecular function. Reason: The G-subunit/a-subunit interaction links V1 and V0 domains and is relevant to assembly/regulation, but proton transport is the core function. Supporting Evidence: PMID:17360703 similar G1/a1, G3/a1, and G1/a4 interactions were also demonstrated
GO:0005515 protein binding	IPI PMID:12649290 The a-subunit of the V-type H+-ATPase interacts with phospho...	MARK AS OVER ANNOTATED	Summary: The PFK-1 interaction with the a1 subunit is supported, but generic protein binding is an uninformative over-annotation for ATP6V0A1. Reason: Keep the interaction as context for possible metabolic regulation, but do not treat generic protein binding as a core molecular function. Supporting Evidence: PMID:12649290 An in vitro bead-bound PFK-1 pull-down assay showed that this interaction was also true for the ubiquitously expressed a1 subunit.
GO:0046610 lysosomal proton-transporting V-type ATPase, V0 domain	IC file:projects/PROTEOSTASIS/reports/pn_projection/pn_projected_candidate_additions.tsv	NEW	Summary: NEW annotation from conservative PN projection review. ATP6V0A1 already has generic V0-domain and lysosomal membrane/acidification annotations; GO:0046610 adds the lysosomal V0-domain specificity supported by the PN row and independent ATP6V0A1/V-ATPase evidence. Reason: The PN candidate is not accepted merely by propagation. It is retained because ATP6V0A1 is a V0-sector a-subunit, V-ATPase operates on lysosomal/endolysosomal membranes, and ATP6V0A1 variants directly impair lysosomal/endolysosomal acidification. Supporting Evidence: file:projects/PROTEOSTASIS/reports/pn_projection/pn_projected_candidate_additions.tsv ATP6V0A1 GO:0046610 lysosomal proton-transporting V-type ATPase, V0 domain file:human/ATP6V0A1/ATP6V0A1-uniprot.txt proton transport subunit a, a ring of proteolipid subunits PMID:33833240 These data suggested that all ATP6V0A1 missense variants impaired lysosomal acidification in cell lines. PMID:34909687 direct impairment of endolysosome acidification and failure of lysosomal functions.

Core Functions

ATP6V0A1 is the a1 subunit of the V0 membrane sector of V-ATPase and contributes to rotary ATP-driven proton transport by the assembled complex.

Directly Involved In:

proton transmembrane transport

In Complex:

proton-transporting V-type ATPase, V0 domain

Supporting Evidence:

file:human/ATP6V0A1/ATP6V0A1-uniprot.txt
proton transport subunit a, a ring of proteolipid subunits
PMID:33065002
ATP hydrolysis-driven proton pumps that acidify intracellular vesicles
PMID:34909687
responsible for proton translocation

As part of V-ATPase complexes on endolysosomal and synaptic vesicle membranes, ATP6V0A1 supports acidification of lysosomes, endosomes, and synaptic vesicles, with downstream effects on protein degradation, autophagic flux, mTORC1/Notch signaling contexts, and neurotransmitter loading.

Directly Involved In:

lysosomal lumen acidification endosomal lumen acidification synaptic vesicle lumen acidification vacuolar acidification

Cellular Locations:

lysosomal membrane endosome membrane synaptic vesicle membrane

In Complex:

proton-transporting V-type ATPase complex

Supporting Evidence:

file:human/ATP6V0A1/ATP6V0A1-uniprot.txt
acidification of various organelles, such as lysosomes, endosomes
PMID:33065002
pH homeostasis of endosomes and lysosomes
PMID:33833240
These data suggested that all ATP6V0A1 missense variants impaired lysosomal acidification in cell lines.
PMID:33833240
the neurotransmitter content of synaptic vesicles was indeed lowered in Atp6v0a1A512P/A512P mice, presumably due to the reduced proton pump activity.

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000024

Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt

GO_REF:0000107

Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara

PMID:12643545

Proteomic analysis of early melanosomes: identification of novel melanosomal proteins.

PMID:12649290

The a-subunit of the V-type H+-ATPase interacts with phosphofructokinase-1 in humans.

PMID:17081065

Proteomic and bioinformatic characterization of the biogenesis and function of melanosomes.

PMID:17360703

V1 and V0 domains of the human H+-ATPase are linked by an interaction between the G and a subunits.

PMID:19056867

Large-scale proteomics and phosphoproteomics of urinary exosomes.

PMID:22982048

Lipofuscin is formed independently of macroautophagy and lysosomal activity in stress-induced prematurely senescent human fibroblasts.

PMID:23533145

In-depth proteomic analyses of exosomes isolated from expressed prostatic secretions in urine.

PMID:32001091

Structure and Roles of V-type ATPases.

PMID:33065002

Structures of a Complete Human V-ATPase Reveal Mechanisms of Its Assembly.

Human V-ATPase structures support ATP6V0A1/V0 complex membership and ATP-driven proton-pump function.

PMID:7896830

Vacuolar H(+)-ATPase mutants transform cells and define a binding site for the papillomavirus E5 oncoprotein.

Reactome:R-HSA-1222516

Intraphagosomal pH is lowered to 5 by V-ATPase

Reactome:R-HSA-5252133

ATP6AP1 binds V-ATPase

Reactome:R-HSA-6798743

Exocytosis of secretory granule membrane proteins

Reactome:R-HSA-6800426

Exocytosis of ficolin-rich granule membrane proteins

Reactome:R-HSA-74723

Endosome acidification

Reactome:R-HSA-917841

Acidification of Tf:TfR1 containing endosome

PMID:33833240

ATP6V0A1 encoding the a1-subunit of the V0 domain of vacuolar H(+)-ATPases is essential for brain development in humans and mice.

ATP6V0A1 disease variants impair lysosomal acidification and synaptic vesicle neurotransmitter loading in cell and mouse models.

PMID:34909687

Variants in ATP6V0A1 cause progressive myoclonus epilepsy and developmental and epileptic encephalopathy.

ATP6V0A1 variants impair endolysosomal acidification and lysosomal function.

PMID:28024296

mTORC1 and muscle regeneration are regulated by the LINC00961-encoded SPAR polypeptide.

SPAR localizes to late endosome/lysosome, interacts with lysosomal V-ATPase, and negatively regulates amino-acid-stimulated mTORC1 activation.

file:human/ATP6V0A1/ATP6V0A1-uniprot.txt

UniProt record for ATP6V0A1 (Q93050)

file:projects/PROTEOSTASIS/reports/pn_projection/pn_projected_candidate_additions.tsv

Proteostasis PN projected candidate additions for ATP6V0A1

PN projection flags GO:0046610 as more specific than existing ATP6V0A1 GOA annotations.

file:interpro/panther/PTHR11629/PTHR11629-metadata.yaml

PANTHER family PTHR11629 metadata for vacuolar proton ATPases

Suggested Experiments

Experiment: Express tagged ATP6V0A1 isoforms at near-endogenous levels in neurons and quantify colocalization with lysosomal, endosomal, and synaptic vesicle markers together with compartment pH reporters.

Hypothesis: ATP6V0A1 isoforms differ in endolysosomal versus synaptic vesicle targeting in neuronal cells.

Type: isoform-resolved localization and organelle pH assay

Deep Research

Falcon

(ATP6V0A1-deep-research-falcon.md)

this with annotations you find in gene/protein databases, but these can be outdated or inaccurate. Falcon

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Comprehensive Research Report: ATP6V0A1 (V-type Proton ATPase Subunit a1)

Gene Identity Verification

The gene ATP6V0A1 (UniProt: Q93050) in Homo sapiens encodes the V-type proton ATPase 116 kDa subunit a1, which is a critical component of the V0 domain of vacuolar-type H+-ATPases (V-ATPases) (indrawinata2023structuralandfunctional pages 1-2, aoto2021atp6v0a1encodingthe pages 1-2). The protein belongs to the V-ATPase 116 kDa subunit family and contains the characteristic V_ATPase_I domain, confirming the correct gene identity as specified in the UniProt annotation. ATP6V0A1 represents the neuronal isoform (a1) of the a-subunit, distinguishing it from other mammalian isoforms (a2, a3, a4) that localize to different cellular compartments and tissues (indrawinata2023structuralandfunctional pages 1-2, tuli2023thecytosolicnterminal pages 1-2, chen2024thedifferentroles pages 2-4).

Primary Function and Molecular Mechanism

Enzymatic Activity and Substrate Specificity

ATP6V0A1 functions as the largest membrane subunit (~110 kDa) of the V0 domain, which constitutes the integral membrane proton-translocating sector of V-ATPases (indrawinata2023structuralandfunctional pages 1-2, wang2020structuresofa pages 1-3). The primary biochemical function of ATP6V0A1 is to enable ATP-driven proton (H+) translocation from the cytoplasm into the lumen of intracellular organelles, thereby establishing and maintaining acidic pH in these compartments (indrawinata2023structuralandfunctional pages 2-4, song2020theemergingroles pages 1-2). The transported substrate is exclusively protons, with no direct interaction with other ions or metabolites.

The V-ATPase operates as a rotary molecular machine composed of two main domains: the cytoplasmic V1 domain (subunits A, B, C, D, E, F, G, H) that hydrolyzes ATP, and the membrane-embedded V0 domain (subunits a1, c-ring, d, e, RNaseK, ATP6AP1, ATP6AP2) that translocates protons (wang2020structuresofa pages 1-3, wang2020structuresofa pages 3-5). ATP6V0A1, as part of V0, provides the essential proton entry and exit pathways through two hemichannels formed at the interface between the a1-subunit and the rotating c-ring (indrawinata2023structuralandfunctional pages 2-4).

Mechanistic Details of Proton Transport

The proton translocation mechanism involves several precisely defined steps (indrawinata2023structuralandfunctional pages 2-4):

A proton enters through the cytoplasmic hemichannel formed by ATP6V0A1
The proton binds to (protonates) essential glutamic acid residues on the c-ring subunits (E139 on subunit c or E98 on subunit c″)
ATP hydrolysis in the V1 domain drives clockwise rotation of the c-ring through the lipid bilayer
The rotation brings the protonated glutamate near the critical arginine residue R740 (also numbered R741 in some transcript variants) in ATP6V0A1
R740 deprotonates the glutamate by forming a transient salt bridge, releasing the proton into the luminal hemichannel
The proton exits through the luminal hemichannel lined by residues H748, E794, and R804, entering the organelle lumen

This mechanism achieves approximately 10 protons translocated per 3 ATP molecules hydrolyzed (indrawinata2023structuralandfunctional pages 2-4). The R740/R741 residue is absolutely critical for this function, as demonstrated by severe loss of acidification in cells expressing the recurrent R741Q disease variant and embryonic lethality in homozygous R741Q mouse models (aoto2021atp6v0a1encodingthe pages 1-2, bott2021variantsinatp6v0a1 pages 1-2, aoto2021atp6v0a1encodingthe pages 2-4).

Structural Organization

ATP6V0A1 consists of two distinct domains (tuli2023thecytosolicnterminal pages 1-2, indrawinata2023structuralandfunctional pages 2-4, tuli2023thecytosolicnterminal pages 2-3):

N-terminal cytosolic domain (aNT): A regulatory hub that adopts a dumbbell-shaped structure with two globular ends connected by a coiled-coil. This domain interacts extensively with V1 subunits (E, G, C, H) and serves to bridge the V1 and V0 sectors, coupling ATP hydrolysis to proton pumping. The aNT domain also contains isoform-specific sequences that determine subcellular trafficking and regulation.
C-terminal membrane domain (aCT): Contains eight transmembrane helices, with two lying nearly horizontally in the membrane. This domain forms the proton entry and exit pathways and interacts directly with the rotating c-ring to enable directional proton transport.

Recent cryo-EM structures of human V-ATPase at 2.9-3.1 Å resolution have revealed these architectural features in detail, confirming the conservation of the basic mechanism from yeast to humans while highlighting unique mammalian features such as the ATP6AP1 and ATP6AP2 accessory subunits (wang2020structuresofa pages 1-3, wang2020structuresofa pages 3-5).

Subcellular Localization and Tissue Distribution

Organelle-Specific Localization

ATP6V0A1 exhibits a distinctive subcellular distribution pattern that reflects its specialized functions (aoto2021atp6v0a1encodingthe pages 1-2, chen2024thedifferentroles pages 1-2, chen2024thedifferentroles pages 2-4):

Lysosomes: ATP6V0A1 colocalizes with lysosomal markers such as LAMP1 and LAMP2, where it maintains the acidic pH (4.5-5.0) required for optimal activity of lysosomal hydrolases (aoto2021atp6v0a1encodingthe pages 2-4, song2020theemergingroles pages 1-2).
Endosomes (early and late): Recent evidence demonstrates that ATP6V0A1 preferentially localizes to endosomes and phagosomes, particularly in their early and intermediate maturation stages. This localization pattern distinguishes a1 from the a3 isoform (TCIRG1), which is more predominantly lysosomal (chen2024thedifferentroles pages 1-2, chen2024thedifferentroles pages 2-4). In zebrafish microglia and mouse macrophages, ATP6V0A1/Atp6v0a1 is primarily found on early and late endosomes/phagosomes, where it is essential for the transition from early to late endosomal compartments (chen2024thedifferentroles pages 2-4).
Synaptic vesicles: In neurons, ATP6V0A1 is specifically targeted to synaptic vesicles and presynaptic membranes, where it acidifies vesicles to enable neurotransmitter loading via vesicular neurotransmitter transporters (aoto2021atp6v0a1encodingthe pages 1-2, chen2024thedifferentroles pages 2-4).
Autophagosomes/Autolysosomes: ATP6V0A1 plays a role in the autophagic pathway, particularly in the fusion of autophagosomes with lysosomes and subsequent cargo degradation (aoto2021atp6v0a1encodingthe pages 1-2, song2020theemergingroles pages 1-2).

Tissue Expression Pattern

ATP6V0A1 is strongly and specifically enriched in neuronal tissues, earning its designation as the "neuronal" or "brain-enriched" a-subunit isoform (indrawinata2023structuralandfunctional pages 1-2, aoto2021atp6v0a1encodingthe pages 1-2, falace2024vatpasedysfunctionin pages 1-3, chen2024thedifferentroles pages 2-4). This tissue-specific expression pattern distinguishes it from other a-subunit isoforms:
- a2 (ATP6V0A2): Golgi apparatus and early endosomes
- a3 (TCIRG1/ATP6V0A3): Lysosomes in osteoclasts and immune cells; plasma membrane in osteoclasts
- a4 (ATP6V0A4): Kidney intercalated cells and inner ear

The neuronal enrichment of ATP6V0A1 explains why its dysfunction predominantly manifests as neurodevelopmental disorders and why global knockout in mice causes embryonic lethality, while neuron-specific knockout leads to selective neuronal death with impaired spatial learning and memory (indrawinata2023structuralandfunctional pages 1-2, aoto2021atp6v0a1encodingthe pages 1-2).

Biochemical Pathways and Signaling Networks

1. mTORC1 Nutrient Sensing Pathway

V-ATPases, including ATP6V0A1-containing complexes, serve as scaffolds for mechanistic target of rapamycin complex 1 (mTORC1) signaling on the lysosomal surface (aoto2021atp6v0a1encodingthe pages 1-2, falace2024vatpasedysfunctionin pages 1-3, siefert2025mammalianravecouples pages 1-5). Under nutrient-replete conditions, mTORC1 is recruited to lysosomes via the Ragulator-Rag GTPase complex, which directly interacts with V-ATPase. This localization is essential for mTORC1 activation by growth factors and amino acids. Loss of ATP6V0A1 function in mouse brain leads to reduced mTORC1 signaling, as evidenced by decreased phosphorylation of downstream targets (aoto2021atp6v0a1encodingthe pages 1-2).

When mTORC1 is inactivated by nutrient starvation, the mammalian RAVE (regulator of H+-ATPase of vacuolar and endosomal membranes) complex promotes increased V1-V0 assembly at lysosomes, enhancing acidification and catabolic activity. This represents a rapid adaptive mechanism that couples nutrient availability to lysosomal degradative capacity (siefert2025mammalianravecouples pages 1-5).

2. Autophagy and Protein Quality Control

ATP6V0A1 is essential for multiple steps of the autophagic pathway (aoto2021atp6v0a1encodingthe pages 1-2, kim2023endolysosomalimpairmentby pages 1-2, song2020theemergingroles pages 1-2):

Autophagosome-lysosome fusion: Proper lysosomal acidification is required for efficient fusion of autophagosomes with lysosomes
Autolysosomal degradation: The acidic pH maintained by ATP6V0A1 activates lysosomal proteases (cathepsins) and other hydrolases that degrade autophagic cargo
Autophagic flux: Impaired ATP6V0A1 function leads to accumulation of autophagosomes and lysosomes, indicating disrupted autophagic clearance

In mouse models with ATP6V0A1 variants, accumulated autophagosomes and lysosomes are observed in brain tissue, accompanied by defective proteolytic maturation of cathepsin D and accumulation of autophagy substrates such as SQSTM1/p62 and MAP1LC3B (aoto2021atp6v0a1encodingthe pages 1-2). The V-ATPase also regulates transcription factor EB (TFEB), a master regulator of lysosomal biogenesis and autophagy genes, through its effects on mTORC1 signaling (falace2024vatpasedysfunctionin pages 1-3).

3. Endocytic Pathway and Membrane Trafficking

ATP6V0A1 plays a critical role in endosome maturation and the endocytic pathway (chen2024thedifferentroles pages 1-2, huang2024atp6v0a1dependentcholesterolabsorption pages 1-2, chen2024thedifferentroles pages 2-4):

Early-to-late endosome transition: Acidification by ATP6V0A1 is required for the progressive maturation of early endosomes (pH ~6.0-6.5) to late endosomes (pH ~5.5-6.0). Deficiency of Atp6v0a1 in zebrafish and mouse cells causes defective phagosome/endosome maturation, with accumulation at early stages (chen2024thedifferentroles pages 2-4).
Endosome-to-lysosome fusion: While ATP6V0A1 primarily regulates early stages, the a3 isoform is more critical for late endosome-lysosome fusion, demonstrating functional specialization among isoforms (chen2024thedifferentroles pages 2-4).
Receptor-ligand dissociation: The acidic pH in endosomes promotes dissociation of receptor-ligand complexes, enabling receptor recycling and ligand degradation (song2020theemergingroles pages 1-2).

4. Cholesterol Metabolism and Immune Regulation

Recent work has identified a novel role for ATP6V0A1 in cellular cholesterol homeostasis and immune regulation (huang2024atp6v0a1dependentcholesterolabsorption pages 1-2). In colorectal cancer cells, ATP6V0A1 facilitates exogenous cholesterol absorption through RABGEF1-dependent endosome maturation. This leads to:

Cholesterol accumulation in the endoplasmic reticulum
Elevated production of 24-hydroxycholesterol (24-OHC)
Activation of liver X receptor (LXR) signaling
Upregulation of TGF-β1 secretion
Immunosuppression of memory CD8+ T cells in the tumor microenvironment

This pathway represents a mechanism by which tumor cells exploit ATP6V0A1-dependent endosomal function to evade immune surveillance (huang2024atp6v0a1dependentcholesterolabsorption pages 1-2).

5. pH Homeostasis and Coupled Transport

The fundamental role of ATP6V0A1 is maintaining organelle acidification, which supports numerous pH-dependent processes (chen2025theemergingroles pages 1-2, song2020theemergingroles pages 1-2):

Enzyme activation: Lysosomal hydrolases require acidic pH for optimal catalytic activity
Protein sorting and trafficking: pH gradients facilitate protein sorting in the secretory and endocytic pathways
Coupled transport: The proton gradient generated by V-ATPase drives secondary active transport of small molecules (neurotransmitters, metabolites) via H+-coupled antiporters and symporters
Neurotransmitter loading: In synaptic vesicles, the electrochemical gradient created by V-ATPase powers vesicular neurotransmitter transporters (VGLUTs, VMATs, VGAT)

Biological Processes and Disease Associations

Table: This table compiles key structural, mechanistic, localization, and complex-level features of human ATP6V0A1, emphasizing how the a1 subunit supports proton translocation and neuronal endolysosomal function. It is useful as a concise reference for functional annotation and interpretation of disease-associated variants.

Disease / association	Variant(s) or molecular context	Inheritance / case pattern	Core clinical features	Model or experimental evidence	Cellular / molecular consequence	Key source citation
Developmental and epileptic encephalopathy (DEE)	R741Q (also reported as R740Q depending on transcript numbering)	Typically de novo heterozygous; recurrent and among the most frequently reported ATP6V0A1 variants	Early developmental delay, infantile-onset seizures, severe epileptic encephalopathy, profound intellectual disability in many cases; often intractable epilepsy (aoto2021atp6v0a1encodingthe pages 1-2, bott2021variantsinatp6v0a1 pages 1-2, aoto2021atp6v0a1encodingthe pages 2-4)	Stable cell lines expressing mutant ATP6V0A1 show impaired lysosomal acidification; homozygous Atp6v0a1 R741Q mice show embryonic lethality (aoto2021atp6v0a1encodingthe pages 1-2, aoto2021atp6v0a1encodingthe pages 2-4)	Direct impairment of proton transport through the V-ATPase a1 subunit; defective endolysosomal acidification, failed lysosomal hydrolysis, autophagic dysfunction (indrawinata2023structuralandfunctional pages 1-2, bott2021variantsinatp6v0a1 pages 1-2, indrawinata2023structuralandfunctional pages 2-4)	(aoto2021atp6v0a1encodingthe pages 1-2, bott2021variantsinatp6v0a1 pages 1-2, indrawinata2023structuralandfunctional pages 2-4, aoto2021atp6v0a1encodingthe pages 2-4)
DEE with recessive / hypomorphic ATP6V0A1 dysfunction	A512P plus deletion of ATP6V0A1 exons; N534D plus splice-site variant	Biallelic; one likely loss-of-function allele plus one missense / hypomorphic allele	Neonatal or early infantile seizure onset, severe developmental impairment, profound intellectual disability, progressive brain atrophy including cerebellar involvement in some individuals (aoto2021atp6v0a1encodingthe pages 1-2, aoto2021atp6v0a1encodingthe pages 2-4)	Cell models expressing A512P or N534D show reduced lysosomal acidification; homozygous Atp6v0a1 A512P mice die early postnatally and show major brain abnormalities (aoto2021atp6v0a1encodingthe pages 1-2, aoto2021atp6v0a1encodingthe pages 2-4)	Lysosomal dysfunction, cell death, accumulation of autophagosomes and lysosomes, reduced mTORC1 signaling, reduced synaptic connectivity, lower neurotransmitter content in synaptic vesicles (aoto2021atp6v0a1encodingthe pages 1-2)	(aoto2021atp6v0a1encodingthe pages 1-2, aoto2021atp6v0a1encodingthe pages 2-4)
Progressive myoclonus epilepsy (PME) with ataxia	Multiple biallelic ATP6V0A1 variants; study highlights compound heterozygous and other recessive alleles in affected families	Biallelic / recessive	Early-onset PME, ataxia, epilepsy; phenotype generally distinct from de novo severe DEE cases (bott2021variantsinatp6v0a1 pages 1-2, bott2021variantsinatp6v0a1 pages 2-3)	Largest cohort study identified 17 affected individuals from 14 families, including 5 with biallelic variants presenting PME (bott2021variantsinatp6v0a1 pages 1-2, bott2021variantsinatp6v0a1 pages 2-3)	Endolysosomal acidification failure linked to ATP6V0A1 dysfunction; mechanistic overlap with lysosomal disease and autophagic impairment (bott2021variantsinatp6v0a1 pages 1-2, bott2021variantsinatp6v0a1 pages 2-3)	(bott2021variantsinatp6v0a1 pages 1-2, bott2021variantsinatp6v0a1 pages 2-3)
ATP6V0A1-related neurodevelopmental disease spectrum	Recurrent R741Q/R740Q plus other missense and biallelic variants	Dominant de novo and recessive patterns both occur	Broad spectrum spanning severe DEE to PME; epilepsy, developmental impairment, cerebellar and cerebral abnormalities, variable ambulatory status (indrawinata2023structuralandfunctional pages 1-2, aoto2021atp6v0a1encodingthe pages 1-2, bott2021variantsinatp6v0a1 pages 1-2)	Review synthesis notes global knockout causes embryonic lethality; pyramidal neuron-specific loss causes neuronal death and impaired spatial / learning memory (indrawinata2023structuralandfunctional pages 1-2)	ATP6V0A1 dysfunction compromises lysosomal and autophagic activities, leading to neuronal vulnerability and cell death (indrawinata2023structuralandfunctional pages 1-2, falace2024vatpasedysfunctionin pages 1-3)	(indrawinata2023structuralandfunctional pages 1-2, falace2024vatpasedysfunctionin pages 1-3)
Structural disease mechanism for pathogenic ATP6V0A1 variants	R740/R741 is a key proton-transfer residue; A512P and N534D are disease-associated missense changes	Mechanistic interpretation from structure plus human genetics	Explains why some variants cause severe encephalopathy while others act as hypomorphic recessive alleles (indrawinata2023structuralandfunctional pages 1-2, aoto2021atp6v0a1encodingthe pages 1-2)	Structural review links R740 to deprotonation of glutamates in the c-ring during proton translocation (indrawinata2023structuralandfunctional pages 2-4)	Loss of proton translocation efficiency, defective organelle acidification, downstream autophagic and lysosomal failure (indrawinata2023structuralandfunctional pages 2-4)	(indrawinata2023structuralandfunctional pages 1-2, indrawinata2023structuralandfunctional pages 2-4)
Neurodegeneration / neuronal vulnerability associated with ATP6V0A1 dysfunction	Human pathogenic variants; neuronal loss-of-function models	Not a single Mendelian phenotype here, but a mechanistic disease axis	Neurons are especially vulnerable because of high dependence on lysosomal homeostasis and vesicle acidification; neurodevelopmental and degenerative manifestations can coexist (falace2024vatpasedysfunctionin pages 1-3)	Brain-focused review integrates human and model data for ATP6V0A1 and related V-ATPase genes (falace2024vatpasedysfunctionin pages 1-3)	Altered H+ transport, impaired lysosomal catabolism, defective membrane trafficking, impaired neurotransmitter loading, neurodegeneration (falace2024vatpasedysfunctionin pages 1-3)	(falace2024vatpasedysfunctionin pages 1-3)
Alzheimer disease–related endolysosomal dysfunction involving V-ATPase	Not ATP6V0A1 mutation-specific; disease context involves pathogenic Aβ / Tau disrupting V-ATPase function	Acquired neurodegenerative context rather than inherited ATP6V0A1 syndrome	Endolysosomal enlargement and dysfunction are linked to neurotoxicity in AD models and brains (kim2023endolysosomalimpairmentby pages 1-2)	Aβ and Tau-associated impairment of V-ATPase activity was shown in neurons and AD models; rescue via HYAL-CD44 axis improved pathology (kim2023endolysosomalimpairmentby pages 1-2)	Endolysosomal dysfunction, impaired proteolytic maturation, substrate accumulation, lysosomal membrane damage; relevant as a broader V-ATPase neurodegeneration mechanism complementing ATP6V0A1 genetic disease (kim2023endolysosomalimpairmentby pages 1-2)	(kim2023endolysosomalimpairmentby pages 1-2)

Table: This table summarizes the main ATP6V0A1-associated disease phenotypes, representative pathogenic variants, and the experimental evidence linking those variants to lysosomal acidification defects and neurodevelopmental disease. It is useful for connecting genotype, clinical presentation, and molecular mechanism.

Developmental and Epileptic Encephalopathy (DEE)

The most prominent disease association is with developmental and epileptic encephalopathy caused by de novo heterozygous variants, particularly the recurrent R741Q (R740Q) mutation (aoto2021atp6v0a1encodingthe pages 1-2, bott2021variantsinatp6v0a1 pages 1-2, aoto2021atp6v0a1encodingthe pages 2-4). This variant accounts for approximately 50% of identified ATP6V0A1 mutations and causes:

Severe developmental delay and profound intellectual disability
Early-onset epilepsy (often infantile spasms or other epileptic encephalopathy patterns)
Intractable seizures
Progressive brain atrophy in some cases
Hypotonia as an early presenting feature

The R741Q mutation directly impairs the critical arginine residue responsible for proton transfer, causing failure of lysosomal acidification and autophagy. Cell models expressing R741Q show significantly reduced LysoTracker staining and defective proteolytic maturation of cathepsin D. Homozygous R741Q mice exhibit embryonic lethality, while heterozygous mice show intermediate phenotypes, underscoring the dominant effect of this variant (aoto2021atp6v0a1encodingthe pages 1-2, aoto2021atp6v0a1encodingthe pages 2-4).

Progressive Myoclonus Epilepsy (PME)

Biallelic variants in ATP6V0A1, typically comprising one loss-of-function allele and one hypomorphic missense variant (such as A512P or N534D), cause early-onset progressive myoclonus epilepsy with ataxia (bott2021variantsinatp6v0a1 pages 1-2). This represents a somewhat distinct phenotype from the severe DEE caused by de novo dominant variants, suggesting that residual ATP6V0A1 function modifies disease severity. Mouse models homozygous for the A512P variant show early postnatal lethality with severe lysosomal dysfunction, accumulated autophagosomes, reduced synaptic connectivity, and decreased neurotransmitter content in synaptic vesicles (aoto2021atp6v0a1encodingthe pages 1-2).

Neurodevelopmental Consequences

The essential nature of ATP6V0A1 for brain development is demonstrated by multiple lines of evidence (indrawinata2023structuralandfunctional pages 1-2, aoto2021atp6v0a1encodingthe pages 1-2, falace2024vatpasedysfunctionin pages 1-3):

Global knockout: Embryonic lethality in mice, indicating essential developmental functions
Neuron-specific knockout: Selective neuronal death, brain atrophy, and impaired learning and memory
Pathogenic variants in humans: Spectrum from severe DEE to PME, with common features of epilepsy, intellectual disability, and motor impairment

The mechanisms underlying these phenotypes include:
- Lysosomal dysfunction and impaired protein degradation
- Defective autophagy leading to accumulation of damaged proteins and organelles
- Reduced synaptic vesicle acidification affecting neurotransmitter loading
- Decreased synaptic connectivity and altered neuronal network function
- Cell death due to proteotoxic stress

Alzheimer's Disease and Neurodegeneration

While not caused by ATP6V0A1 mutations, V-ATPase dysfunction plays a role in Alzheimer's disease pathogenesis (kim2023endolysosomalimpairmentby pages 1-2). Amyloid-β oligomers and hyperphosphorylated tau directly bind to V-ATPase subunits (ATP6V0C and ATP6V1B2), disrupting V-ATPase activity and causing:

Endolysosomal dysfunction and enlargement
Impaired autophagy
Lysosomal membrane damage
Neuronal death

This highlights that ATP6V0A1 and V-ATPase function are critical for neuronal health beyond genetic disorders, with implications for age-related neurodegeneration (kim2023endolysosomalimpairmentby pages 1-2).

Cancer and Immune Evasion

Beyond neurological disease, ATP6V0A1 has been implicated in cancer biology. Enhanced V-ATPase expression and activity in cancer cells contributes to tumor growth, metastasis, and drug resistance through multiple mechanisms (huang2024atp6v0a1dependentcholesterolabsorption pages 1-2, chen2024vatpaseincancer pages 1-3):

Acidification of the tumor microenvironment promoting invasion
Facilitation of cholesterol-dependent immunosuppression
Lysosomal sequestration of chemotherapeutic drugs
Support for cancer cell metabolism via mTORC1 and AMPK pathways

The identification of daclatasvir, a clinically approved anti-hepatitis C virus drug, as an ATP6V0A1 inhibitor that enhances anti-tumor immunity suggests potential therapeutic applications (huang2024atp6v0a1dependentcholesterolabsorption pages 1-2).

Experimental Evidence and Model Systems

Mouse Models

Multiple mouse models have been generated to study ATP6V0A1 function (aoto2021atp6v0a1encodingthe pages 1-2):

Global knockout (Atp6v0a1-/-): Embryonic lethal, demonstrating essential developmental function
Neuron-specific conditional knockout: Neuronal death, brain atrophy, impaired spatial learning and memory
Homozygous R741Q knock-in: Embryonic lethal
Homozygous A512P knock-in: Early postnatal lethality with severe brain phenotypes including:
Lysosomal dysfunction and cell death
Accumulated autophagosomes and lysosomes
Reduced mTORC1 signaling
Decreased synaptic connectivity
Lower neurotransmitter content in synaptic vesicles

These models confirm that ATP6V0A1 is essential for neuronal survival, synaptic function, and brain development, validating its role in human disease.

Cellular Models

Stable cell lines (HEK293FT, N2A neuroblastoma) expressing wild-type or mutant ATP6V0A1 have been instrumental in characterizing disease mechanisms (aoto2021atp6v0a1encodingthe pages 2-4):

Mutant proteins (R741Q, A512P, N534D) show normal subcellular localization with ATP6V1A and LAMP2
LysoTracker and LysoSensor assays demonstrate significantly impaired lysosomal acidification
Accumulation of autophagy substrates (SQSTM1, LC3) and defective cathepsin D maturation
Enlarged lysosomes and increased lysosomal membrane damage markers (galectin-3)

Caenorhabditis elegans

The R740Q mutation causes severe developmental defects and autophagic dysfunction in C. elegans, providing a tractable genetic model for studying disease mechanisms and potential therapeutic interventions (bott2021variantsinatp6v0a1 pages 1-2).

Current Understanding and Recent Developments (2023-2024)

Recent structural, functional, and clinical studies have significantly advanced our understanding of ATP6V0A1:

Structural insights (2020-2024): High-resolution cryo-EM structures of human V-ATPase have defined the precise architecture of ATP6V0A1 and its interactions with other subunits, revealing mechanisms of assembly, regulation, and proton transport (wang2020structuresofa pages 1-3, wang2020structuresofa pages 3-5).
RAVE complex and assembly (2025): Characterization of mammalian RAVE (Dmxl1/2, Wdr7, Rogdi) as an essential V-ATPase assembly factor that couples acidification to nutrient signaling and organelle function (siefert2025mammalianravecouples pages 1-5).
Isoform-specific functions (2024): Clarification that ATP6V0A1 and ATP6V0A3 have distinct subcellular localizations and functions in endosome vs. lysosome maturation, with ATP6V0A1 being critical for early-to-late endosome transition (chen2024thedifferentroles pages 2-4).
Cholesterol-immunity axis (2024): Discovery that ATP6V0A1-dependent endosomal cholesterol absorption drives immunosuppressive signaling in cancer, identifying daclatasvir as a potential therapeutic (huang2024atp6v0a1dependentcholesterolabsorption pages 1-2).
Comprehensive disease characterization (2021-2024): Expansion of the ATP6V0A1 disease spectrum through identification of 17 affected individuals, defining distinct DEE and PME phenotypes and establishing genotype-phenotype correlations (bott2021variantsinatp6v0a1 pages 1-2, falace2024vatpasedysfunctionin pages 1-3).
Cardiovascular implications (2025): Recognition that V-ATPase-dependent lysosomal acidification plays roles in cardiovascular disease, expanding the disease spectrum beyond neurological disorders (chen2025theemergingroles pages 1-2).

Summary

ATP6V0A1 encodes the neuronal a1-subunit of the V0 domain of V-ATPases, functioning as a proton pump that acidifies lysosomes, endosomes, synaptic vesicles, and other organelles. Its primary molecular function is to provide the proton translocation pathway through cytoplasmic and luminal hemichannels, with the critical R740/R741 residue mediating proton transfer from the rotating c-ring. The protein is predominantly expressed in neurons and localizes to endolysosomes and synaptic vesicles, where it maintains acidic pH essential for protein degradation, autophagy, endosome maturation, and neurotransmitter loading.

ATP6V0A1 participates in key cellular pathways including mTORC1 nutrient sensing, autophagy, endocytic trafficking, and cholesterol metabolism. Pathogenic variants, particularly the recurrent R741Q mutation, cause severe developmental and epileptic encephalopathy through impaired lysosomal acidification, defective autophagy, and neuronal dysfunction. The essential nature of ATP6V0A1 for brain development is evidenced by embryonic lethality in global knockout mice and severe neurological disease in humans with ATP6V0A1 variants. Recent structural and functional studies have illuminated the precise mechanisms of proton transport and revealed novel roles in immune regulation and cancer biology, establishing ATP6V0A1 as a critical hub for cellular pH homeostasis and neuronal function.

References

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(tuli2023thecytosolicnterminal pages 1-2): Farzana Tuli and Patricia M. Kane. The cytosolic n-terminal domain of v-atpase a-subunits is a regulatory hub targeted by multiple signals. Frontiers in Molecular Biosciences, Jun 2023. URL: https://doi.org/10.3389/fmolb.2023.1168680, doi:10.3389/fmolb.2023.1168680. This article has 10 citations.
(chen2024thedifferentroles pages 2-4): Qi Chen, Hanjing Kou, Doris Lou Demy, Wei Liu, Jianchao Li, Zilong Wen, Philippe Herbomel, Zhibin Huang, Wenqing Zhang, and Jin Xu. The different roles of v-atpase a subunits in phagocytosis/endocytosis and autophagy. Autophagy, 20:2297-2313, Jun 2024. URL: https://doi.org/10.1080/15548627.2024.2366748, doi:10.1080/15548627.2024.2366748. This article has 27 citations and is from a domain leading peer-reviewed journal.
(wang2020structuresofa pages 1-3): Longfei Wang, Di Wu, Carol V. Robinson, Hao Wu, and Tian-Min Fu. Structures of a complete human v-atpase reveal mechanisms of its assembly. Molecular Cell, 80:501-511.e3, Nov 2020. URL: https://doi.org/10.1016/j.molcel.2020.09.029, doi:10.1016/j.molcel.2020.09.029. This article has 184 citations and is from a highest quality peer-reviewed journal.
(indrawinata2023structuralandfunctional pages 2-4): Karen Indrawinata, Peter Argiropoulos, and Shuzo Sugita. Structural and functional understanding of disease-associated mutations in v-atpase subunit a1 and other isoforms. Frontiers in Molecular Neuroscience, Jul 2023. URL: https://doi.org/10.3389/fnmol.2023.1135015, doi:10.3389/fnmol.2023.1135015. This article has 16 citations.
(song2020theemergingroles pages 1-2): Qiaoyun Song, Bo Meng, Haidong Xu, and Zixu Mao. The emerging roles of vacuolar-type atpase-dependent lysosomal acidification in neurodegenerative diseases. Translational Neurodegeneration, May 2020. URL: https://doi.org/10.1186/s40035-020-00196-0, doi:10.1186/s40035-020-00196-0. This article has 255 citations and is from a domain leading peer-reviewed journal.
(wang2020structuresofa pages 3-5): Longfei Wang, Di Wu, Carol V. Robinson, Hao Wu, and Tian-Min Fu. Structures of a complete human v-atpase reveal mechanisms of its assembly. Molecular Cell, 80:501-511.e3, Nov 2020. URL: https://doi.org/10.1016/j.molcel.2020.09.029, doi:10.1016/j.molcel.2020.09.029. This article has 184 citations and is from a highest quality peer-reviewed journal.
(bott2021variantsinatp6v0a1 pages 1-2): Laura C Bott, Mitra Forouhan, Maria Lieto, Ambre J Sala, Ruth Ellerington, Janel O Johnson, Alfina A Speciale, Chiara Criscuolo, Alessandro Filla, David Chitayat, Ebba Alkhunaizi, Patrick Shannon, Andrea H Nemeth, Domenica Taruscio, Marco Salvatore, Agata Polizzi, Federica Censi, Giovanna Floridia, Giuseppe Novelli, Erica Daina, Alessandra Ferlini, Marcella Neri, Dario Roccatello, Simone Baldovino, Elisa Menegatti, Francesco Angelucci, Wooi Fang Lim, Pasquale Striano, Federico Zara, Ingo Helbig, Mikko Muona, Carolina Courage, Anna-Elina Lehesjoki, Samuel F Berkovic, Nancy Pinnell, Dallas Reed, Peter D Turnpenny, Jacqueline Eason, Leah Fleming, Kirsty McWalter, Kali Juliette, Paul J Benke, Xilma Ortiz-Gonzalez, Sarah Mckeown, Amisha B Patel, Matthew Osmond, Jagdeep S Walia, Xianru Jiao, Zhixian Yang, Boris Keren, Charles Perrine, Ashish Deshwar, Kenneth H Fischbeck, Francesco Brancati, Richard I Morimoto, Matthew J A Wood, and Carlo Rinaldi. Variants in atp6v0a1 cause progressive myoclonus epilepsy and developmental and epileptic encephalopathy. Brain Communications, Oct 2021. URL: https://doi.org/10.1093/braincomms/fcab245, doi:10.1093/braincomms/fcab245. This article has 37 citations and is from a peer-reviewed journal.
(aoto2021atp6v0a1encodingthe pages 2-4): Kazushi Aoto, Mitsuhiro Kato, Tenpei Akita, Mitsuko Nakashima, Hiroki Mutoh, Noriyuki Akasaka, Jun Tohyama, Yoshiko Nomura, Kyoko Hoshino, Yasuhiko Ago, Ryuta Tanaka, Orna Epstein, Revital Ben-Haim, Eli Heyman, Takehiro Miyazaki, Hazrat Belal, Shuji Takabayashi, Chihiro Ohba, Atsushi Takata, Takeshi Mizuguchi, Satoko Miyatake, Noriko Miyake, Atsuo Fukuda, Naomichi Matsumoto, and Hirotomo Saitsu. Atp6v0a1 encoding the a1-subunit of the v0 domain of vacuolar h+-atpases is essential for brain development in humans and mice. Nature Communications, Apr 2021. URL: https://doi.org/10.1038/s41467-021-22389-5, doi:10.1038/s41467-021-22389-5. This article has 71 citations and is from a highest quality peer-reviewed journal.
(tuli2023thecytosolicnterminal pages 2-3): Farzana Tuli and Patricia M. Kane. The cytosolic n-terminal domain of v-atpase a-subunits is a regulatory hub targeted by multiple signals. Frontiers in Molecular Biosciences, Jun 2023. URL: https://doi.org/10.3389/fmolb.2023.1168680, doi:10.3389/fmolb.2023.1168680. This article has 10 citations.
(chen2024thedifferentroles pages 1-2): Qi Chen, Hanjing Kou, Doris Lou Demy, Wei Liu, Jianchao Li, Zilong Wen, Philippe Herbomel, Zhibin Huang, Wenqing Zhang, and Jin Xu. The different roles of v-atpase a subunits in phagocytosis/endocytosis and autophagy. Autophagy, 20:2297-2313, Jun 2024. URL: https://doi.org/10.1080/15548627.2024.2366748, doi:10.1080/15548627.2024.2366748. This article has 27 citations and is from a domain leading peer-reviewed journal.
(falace2024vatpasedysfunctionin pages 1-3): Antonio Falace, Greta Volpedo, Marcello Scala, Federico Zara, Pasquale Striano, and Anna Fassio. V-atpase dysfunction in the brain: genetic insights and therapeutic opportunities. Cells, 13:1441, Aug 2024. URL: https://doi.org/10.3390/cells13171441, doi:10.3390/cells13171441. This article has 22 citations.
(siefert2025mammalianravecouples pages 1-5): Nora S. Siefert, Andrea Zanotti, Anastasija Paneva, Martin Schneider, Dominic Helm, and Wilhelm Palm. Mammalian rave couples v-atpase assembly to organelle acidification and function. bioRxiv, Dec 2025. URL: https://doi.org/10.64898/2025.12.10.693398, doi:10.64898/2025.12.10.693398. This article has 1 citations.
(kim2023endolysosomalimpairmentby pages 1-2): Seo-Hyun Kim, Young-Sin Cho, Youbin Kim, Jisu Park, Seung-Min Yoo, Jimin Gwak, Youngwon Kim, Youngdae Gwon, Tae-in Kam, and Yong-Keun Jung. Endolysosomal impairment by binding of amyloid beta or mapt/tau to v-atpase and rescue via the hyal-cd44 axis in alzheimer disease. Autophagy, 19:2318-2337, Feb 2023. URL: https://doi.org/10.1080/15548627.2023.2181614, doi:10.1080/15548627.2023.2181614. This article has 59 citations and is from a domain leading peer-reviewed journal.
(huang2024atp6v0a1dependentcholesterolabsorption pages 1-2): Tu-Xiong Huang, Hui-Si Huang, Shao-Wei Dong, Jia-Yan Chen, Bin Zhang, Hua-Hui Li, Tian-Tian Zhang, Qiang Xie, Qiao-Yun Long, Yang Yang, Lin-Yuan Huang, Pan Zhao, Jiong Bi, Xi-Feng Lu, Fan Pan, Chang Zou, and Li Fu. Atp6v0a1-dependent cholesterol absorption in colorectal cancer cells triggers immunosuppressive signaling to inactivate memory cd8+ t cells. Nature Communications, Jul 2024. URL: https://doi.org/10.1038/s41467-024-50077-7, doi:10.1038/s41467-024-50077-7. This article has 50 citations and is from a highest quality peer-reviewed journal.
(chen2025theemergingroles pages 1-2): Yan-Yan Chen, Cai-Xia Liu, Hai-Xin Liu, and Shi-Yuan Wen. The emerging roles of vacuolar-type atpase-dependent lysosomal acidification in cardiovascular disease. Biomolecules, 15:525, Apr 2025. URL: https://doi.org/10.3390/biom15040525, doi:10.3390/biom15040525. This article has 17 citations.
(chen2024vatpaseincancer pages 1-3): Tingting Chen, Xiaotan Lin, Shuo Lu, and Bo Li. V-atpase in cancer: mechanistic insights and therapeutic potentials. Cell Communication and Signaling : CCS, Dec 2024. URL: https://doi.org/10.1186/s12964-024-01998-9, doi:10.1186/s12964-024-01998-9. This article has 25 citations.
(bott2021variantsinatp6v0a1 pages 2-3): Laura C Bott, Mitra Forouhan, Maria Lieto, Ambre J Sala, Ruth Ellerington, Janel O Johnson, Alfina A Speciale, Chiara Criscuolo, Alessandro Filla, David Chitayat, Ebba Alkhunaizi, Patrick Shannon, Andrea H Nemeth, Domenica Taruscio, Marco Salvatore, Agata Polizzi, Federica Censi, Giovanna Floridia, Giuseppe Novelli, Erica Daina, Alessandra Ferlini, Marcella Neri, Dario Roccatello, Simone Baldovino, Elisa Menegatti, Francesco Angelucci, Wooi Fang Lim, Pasquale Striano, Federico Zara, Ingo Helbig, Mikko Muona, Carolina Courage, Anna-Elina Lehesjoki, Samuel F Berkovic, Nancy Pinnell, Dallas Reed, Peter D Turnpenny, Jacqueline Eason, Leah Fleming, Kirsty McWalter, Kali Juliette, Paul J Benke, Xilma Ortiz-Gonzalez, Sarah Mckeown, Amisha B Patel, Matthew Osmond, Jagdeep S Walia, Xianru Jiao, Zhixian Yang, Boris Keren, Charles Perrine, Ashish Deshwar, Kenneth H Fischbeck, Francesco Brancati, Richard I Morimoto, Matthew J A Wood, and Carlo Rinaldi. Variants in atp6v0a1 cause progressive myoclonus epilepsy and developmental and epileptic encephalopathy. Brain Communications, Oct 2021. URL: https://doi.org/10.1093/braincomms/fcab245, doi:10.1093/braincomms/fcab245. This article has 37 citations and is from a peer-reviewed journal.

📚 Additional Documentation

Notes

(ATP6V0A1-notes.md)

ATP6V0A1 notes

2026-06-03 - Proteostasis PN review

Deep research status: Falcon deep research has now completed successfully
(ATP6V0A1-deep-research-falcon.md, 27 citations); see the synthesis section at
the end of this file. The original PN-batch attempt timed out before the
deep_research_unified tool bugs were fixed. This review uses that report
together with fetched UniProt, GOA, cached publications, Reactome records,
Panther family data, and the PN projection reports.

Core biology: ATP6V0A1 encodes the a1 subunit of the V0 membrane sector of
V-ATPase. UniProt describes it as a "Subunit of the V0 complex of
vacuolar(H+)-ATPase" and says V-ATPase acidifies "lysosomes, endosomes, the
trans-Golgi network, and secretory granules, including synaptic vesicles"
[file:human/ATP6V0A1/ATP6V0A1-uniprot.txt, "Subunit of the V0 complex of
vacuolar(H+)-ATPase"; file:human/ATP6V0A1/ATP6V0A1-uniprot.txt,
"acidification of various organelles, such as lysosomes, endosomes"]. The human
V-ATPase structure paper frames V-ATPases as "ATP hydrolysis-driven proton
pumps" and says organellar V-ATPases maintain "pH homeostasis of endosomes and
lysosomes" [PMID:33065002, "ATP hydrolysis-driven proton pumps that acidify
intracellular vesicles"; PMID:33065002, "pH homeostasis of endosomes and
lysosomes"].

ATP6V0A1-specific disease/function papers support the same function. Aoto et
al. show that ATP6V0A1 missense variants impair lysosomal acidification in cell
lines and that mutant mice have lysosomal dysfunction, autophagy defects,
reduced mTORC1 signaling, synaptic connectivity defects, and lowered
neurotransmitter content of synaptic vesicles [PMID:33833240, "These data
suggested that all ATP6V0A1 missense variants impaired lysosomal acidification
in cell lines."; PMID:33833240, "the neurotransmitter content of synaptic
vesicles was indeed lowered"]. Bott et al. similarly link ATP6V0A1 variants to
"direct impairment of endolysosome acidification and failure of lysosomal
functions" [PMID:34909687, "direct impairment of endolysosome acidification and
failure of lysosomal functions."].

PN projection: ATP6V0A1 appears in the PN projection under
Autophagy-Lysosome Pathway > Pre-initiation autophagy signaling > mTORC1 pathway, upstream > Nutrient sensing > V0 lysosomal v-ATPase proton pump component, projecting GO:0046610 lysosomal proton-transporting V-type ATPase, V0 domain as more_specific_than_existing_goa
[file:projects/PROTEOSTASIS/reports/pn_projection/pn_projected_candidate_additions.tsv,
"ATP6V0A1 GO:0046610 lysosomal proton-transporting V-type ATPase, V0 domain"].
This projection was accepted conservatively as a NEW candidate only because it
is independently supported by ATP6V0A1/V-ATPase evidence. The PN resource was
not used to add broader mTORC1 or nutrient-sensing process annotations.

Curation decisions:

Accept V-ATPase complex/V0-domain membership, contributes-to rotary
proton-transporting ATPase activity, proton transmembrane transport, lysosomal
and endosomal acidification, and synaptic vesicle acidification.
Add GO:0046610 lysosomal proton-transporting V-type ATPase, V0 domain as a
conservative PN-supported NEW annotation.
Keep plasma membrane, secretory granule, ficolin-1-rich granule, phagocytic
vesicle, clathrin-coated vesicle, perinuclear cytoplasm, melanosome, and
ATPase-binding rows as non-core where supported.
Mark generic cytoplasm, membrane, and extracellular exosome rows as
over-annotated relative to the more informative organelle membrane and complex
terms.
Remove the PMID:7896830 protein binding row because the paper supports
papillomavirus E5 binding to the 16 kDa V-ATPase proteolipid subunit, not to
ATP6V0A1 [PMID:7896830, "The 16K subunit of the vacuolar H(+)-ATPase binds
specifically"].
Mark the PFK-1 protein binding row as over-annotated. The a1 interaction is
real, but generic protein binding is not an informative ATP6V0A1 molecular
function [PMID:12649290, "An in vitro bead-bound PFK-1 pull-down assay showed
that this interaction was also true for the ubiquitously expressed a1
subunit."].

Falcon deep research synthesis (2026-06-21)

The Falcon report (file:human/ATP6V0A1/ATP6V0A1-deep-research-falcon.md)
corroborates the core a1-subunit / lysosomal-acidification biology above and adds
mechanistic and pathway detail.

Mechanistic MF detail — a1 is the proton-conducting subunit, not just a
structural component. Unlike the ATP6AP1/ATP6AP2 accessory subunits, ATP6V0A1
directly builds the proton pathway: its C-terminal membrane domain (aCT, 8 TM
helices, two near-horizontal) forms the cytoplasmic and luminal hemichannels,
and the essential arginine R740/R741 deprotonates the c-ring glutamates
(E139 on c / E98 on c'') as the rotor turns, releasing H+ to the lumen (~10 H+
per 3 ATP). R741Q is a recurrent loss-of-acidification disease variant
(embryonic-lethal when homozygous in mouse), which pins the proton-translocation
activity to this residue (Indrawinata 2023; Aoto 2021 PMID:33833240; Bott 2021
PMID:34909687). This supports annotating ATP6V0A1 with the proton-transmembrane-
transporter / V0 proton-pore activity rather than only "complex component".

N-terminal cytosolic domain (aNT) as the V1-V0 coupling/regulatory hub. The
dumbbell-shaped aNT bridges V1 (subunits E, G, C, H) and V0, couples ATP
hydrolysis to rotation, and carries isoform-specific trafficking sequences
(Tuli 2023) — the structural basis for a1-isoform-specific organelle targeting.

New non-core role — cholesterol absorption / immune evasion (Huang 2024). In
colorectal cancer, ATP6V0A1 drives RABGEF1-dependent endosome maturation and
exogenous cholesterol absorption → ER cholesterol → 24-hydroxycholesterol → LXR
→ TGF-β1 → suppression of memory CD8+ T cells. A genuine but disease/context-
specific downstream consequence of endosomal acidification; keep non-core.

Corroborated (no change to calls): acidification of lysosomes/endosomes/TGN/
secretory & synaptic vesicles; powering H+-coupled neurotransmitter loading
(VGLUT/VMAT/VGAT) and secondary active transport; mTORC1 nutrient sensing;
autophagy/PQC; and the neurological disease spectrum (DEE, progressive myoclonus
epilepsy, neurodevelopmental phenotypes). Net: core call unchanged (V0 a1 subunit
mediating organellar/lysosomal acidification), with sharper mechanistic support.

Pn Notes

(ATP6V0A1-pn-notes.md)

ATP6V0A1 PN Consistency Notes

Generated: 2026-06-18
Project: PROTEOSTASIS
Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
UniProt: Q93050
AIGR review status: COMPLETE
Review batch: proteostasis-batch-2026-06-03 (PR 1381)
Batch change status: added

Source Files Checked

AIGR review YAML: present - genes/human/ATP6V0A1/ATP6V0A1-ai-review.yaml
AIGR review HTML: present - genes/human/ATP6V0A1/ATP6V0A1-ai-review.html
Gene notes: present - genes/human/ATP6V0A1/ATP6V0A1-notes.md
GOA TSV: present - genes/human/ATP6V0A1/ATP6V0A1-goa.tsv
UniProt record: present - genes/human/ATP6V0A1/ATP6V0A1-uniprot.txt
PN dossier: projects/PROTEOSTASIS/reports/phase1_dossiers/ATP6V0A1.md
PN consistency section: projects/PROTEOSTASIS/reports/phase1_dossiers/_sections/ATP6V0A1.md
PN projection report: projects/PROTEOSTASIS/reports/pn_projection/pn_projected_gene_go_summary.tsv
PN mapping audit: projects/PROTEOSTASIS/reports/pn_mapping_audit/current_mapping_scrutiny.tsv

Deep Research Files

No *-deep-research*.md file found in this gene directory.

AIGR Review Snapshot

Description: ATP6V0A1 encodes the a1 isoform of the V0 membrane sector of the vacuolar H+-ATPase. It is a multi-pass membrane subunit that helps assemble the proton-translocation sector of V-ATPase complexes on endolysosomal, synaptic vesicle, secretory vesicle, melanosomal, and specialized plasma membranes. By contributing to ATP-driven proton transport, ATP6V0A1 supports acidification of lysosomes, endosomes, synaptic vesicles, and related organelles; pathogenic variants impair endolysosomal acidification and cause severe neurodevelopmental disease with synaptic and autophagy defects.
Existing/core annotation action counts: ACCEPT: 18; KEEP_AS_NON_CORE: 16; MARK_AS_OVER_ANNOTATED: 5; MODIFY: 1; NEW: 1; REMOVE: 1

PN Consistency Summary

Consistency: Consistent. Notes/review YAML, PN annotation, and PN-node mapping all describe ATP6V0A1 as the brain-enriched V0 a1-subunit of the lysosomal/synaptic-vesicle V-ATPase. Review ACCEPTs generic GO:0033179 ("already consistent with the PN projection") and ADDED GO:0046610 (action: NEW, IC, part_of) as the lysosome-specific refinement. No contradictions.
PN story / NEW pressure: PN's lysosome-specific V0 term (GO:0046610) was more_specific_than_existing GOA; review correctly ADDED it, supported by ATP6V0A1 disease variants impairing lysosomal/endolysosomal acidification (PMID:33833240, 34909687). Generic V0 (GO:0033179) and acidification (GO:0007042) already captured. Verdict: one ADD (GO:0046610), rest already-captured — no over-reach.
Evidence alignment: PN cites the same V-ATPase/mTORC1 review set as ATP6V0C. Review anchors claims to gene-specific disease/functional papers (PMID:33833240 ATP6V0A1 variants; PMID:34909687 endolysosome acidification; PMID:33065002 structure) — more primary and gene-specific than the PN row. Convergent direction.
Verdict: Consistent; PN lysosomal-V0 projection correctly ADDED (NEW GO:0046610). Optional: harmonize NEW-row evidence code with ATP6V0C (IC vs TAS).

Full Consistency Review

UniProt: Q93050 · batch: proteostasis-batch-2026-06-03 · review status: COMPLETE
PN placement: ALP|Lysosomal catabolism|Regulation of lysosomal environment|Lysosomal acidification|V0 lysosomal v-ATPase proton pump component (also ...|Pre-initiation autophagy signaling|mTORC1 pathway, upstream|Nutrient sensing|V0...) ; PN-node mapping: subtype mapped→GO:0046610 lysosomal V0 domain (Pre-init leaf, more_specific_than_existing_goa) / GO:0033179 V0 domain (Lysosomal leaf, already_in_goa_exact); type mapped→GO:0007042 lysosomal lumen acidification.
Consistency: Consistent. Notes/review YAML, PN annotation, and PN-node mapping all describe ATP6V0A1 as the brain-enriched V0 a1-subunit of the lysosomal/synaptic-vesicle V-ATPase. Review ACCEPTs generic GO:0033179 ("already consistent with the PN projection") and ADDED GO:0046610 (action: NEW, IC, part_of) as the lysosome-specific refinement. No contradictions.
PN story / NEW pressure: PN's lysosome-specific V0 term (GO:0046610) was more_specific_than_existing GOA; review correctly ADDED it, supported by ATP6V0A1 disease variants impairing lysosomal/endolysosomal acidification (PMID:33833240, 34909687). Generic V0 (GO:0033179) and acidification (GO:0007042) already captured. Verdict: one ADD (GO:0046610), rest already-captured — no over-reach.
Mapping strategy: Gene supports node mapping; projected lysosomal-V0 term is narrower than the existing generic V0/complex annotations — an appropriate refinement. Notably the review used evidence code IC for the NEW row (vs TAS in the parallel ATP6V0C review) — a minor cross-gene inconsistency in how the same PN-derived lysosomal-V0 refinement is coded.
Evidence alignment: PN cites the same V-ATPase/mTORC1 review set as ATP6V0C. Review anchors claims to gene-specific disease/functional papers (PMID:33833240 ATP6V0A1 variants; PMID:34909687 endolysosome acidification; PMID:33065002 structure) — more primary and gene-specific than the PN row. Convergent direction.
Verdict: Consistent; PN lysosomal-V0 projection correctly ADDED (NEW GO:0046610). Optional: harmonize NEW-row evidence code with ATP6V0C (IC vs TAS).
Recommended edits: [YAML] Consider aligning the GO:0046610 NEW-row evidence code between ATP6V0A1 (IC) and ATP6V0C (TAS) for consistency across the V0 PN refinements (low priority; both are defensible).

PN Dossier Context

review_batch: proteostasis-batch-2026-06-03
review_yaml: genes/human/ATP6V0A1/ATP6V0A1-ai-review.yaml
PN workbook rows: 2

PN row 1: Autophagy-Lysosome Pathway | Pre-initiation autophagy signaling | mTORC1 pathway, upstream | Nutrient sensing | V0 lysosomal v-ATPase proton pump component

UniProt: Q93050
In branches: ALP
Notes: Subunit of the V0 (lysosomal membrane bound) component of the lysosomal v-ATPase. The V0 and V1 components of the v-ATPase assemble during amino acid starvation creating the active v-ATPase that pumps protons into the lysosome for acidification. The v-ATPase also engages in amino acid-dependent interactions with the Ragulator complex. In the presence of amino acids, the v-ATPase-Ragulator complex undergoes a conformational change that results in Ragulator exerting its GEF activity on RAGA/B.
PN references (titles):
- Regulation of mTORC1 by amino acids - ScienceDirect
- Cells | Free Full-Text | SEA and GATOR 10 Years Later | HTML (mdpi.com)
- Eukaryotic V-ATPase: Novel structural findings and functional insights - ScienceDirect
- The emerging roles of vacuolar-type ATPase-dependent Lysosomal acidification in neurodegenerative diseases | Translational Neurodegeneration | Full Text (biomedcentral.com)
PN-node mapping records (path + ancestors):
- [subtype] Autophagy-Lysosome Pathway|Pre-initiation autophagy signaling|mTORC1 pathway, upstream|Nutrient sensing|V0 lysosomal v-ATPase proton pump component
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0046610 lysosomal proton-transporting V-type ATPase, V0 domain]
  rationale: This PN leaf is restricted to V0-sector lysosomal V-ATPase components. The GO lysosomal V0-domain component term is the direct target.
- [type] Autophagy-Lysosome Pathway|Pre-initiation autophagy signaling|mTORC1 pathway, upstream|Nutrient sensing
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a contextual PN role. The label is useful for curator triage, but by itself does not support a universal GO assertion for all member genes beyond curated ancestor or child mappings.
- [group] Autophagy-Lysosome Pathway|Pre-initiation autophagy signaling|mTORC1 pathway, upstream
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a broad PN taxonomy container. The descendants mix components, regulators, context labels, and mechanistic leaves, so propagation should come only from narrower curated nodes.
- [class] Autophagy-Lysosome Pathway|Pre-initiation autophagy signaling
  status=context_only scope=too_broad_to_propagate GO=[GO:0010506 regulation of autophagy]
  rationale: This class organizes upstream signaling inputs to autophagy initiation. Because the subtree contains generic insulin, AMPK, mTORC1, nutrient-sensing, and miscellaneous signaling components, class-level propagation to regulation of autophagy would over-annotate many genes.
- [branch] Autophagy-Lysosome Pathway
  status=no_mapping scope= GO=[]
  rationale: Reviewed as the top-level PN branch. It is a project taxonomy umbrella rather than a direct GO assertion; all propagation must come from manually curated child nodes.

PN row 2: Autophagy-Lysosome Pathway | Lysosomal catabolism | Regulation of lysosomal environment | Lysosomal acidification | V0 lysosomal v-ATPase proton pump component

UniProt: Q93050
In branches: ALP
Notes: Subunit of the V0 (lysosomal membrane bound) component of the lysosomal v-ATPase. The V0 and V1 components of the v-ATPase assemble during amino acid starvation creating the active v-ATPase that pumps protons into the lysosome for acidification. The v-ATPase also engages in amino acid-dependent interactions with the Ragulator complex. In the presence of amino acids, the v-ATPase-Ragulator complex undergoes a conformational change that results in Ragulator exerting its GEF activity on RAGA/B.
PN references (titles):
- Regulation of mTORC1 by amino acids - ScienceDirect
- Cells | Free Full-Text | SEA and GATOR 10 Years Later | HTML (mdpi.com)
- Eukaryotic V-ATPase: Novel structural findings and functional insights - ScienceDirect
- The emerging roles of vacuolar-type ATPase-dependent Lysosomal acidification in neurodegenerative diseases | Translational Neurodegeneration | Full Text (biomedcentral.com)
PN-node mapping records (path + ancestors):
- [subtype] Autophagy-Lysosome Pathway|Lysosomal catabolism|Regulation of lysosomal environment|Lysosomal acidification|V0 lysosomal v-ATPase proton pump component
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0033179 proton-transporting V-type ATPase, V0 domain]
  rationale: This PN subtype denotes the V0-sector component of the lysosomal V-type ATPase. The GO V0-domain component term is the appropriate propagation target.
- [type] Autophagy-Lysosome Pathway|Lysosomal catabolism|Regulation of lysosomal environment|Lysosomal acidification
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0007042 lysosomal lumen acidification]
  rationale: This PN group directly names the lysosomal acidification mechanism. Propagation to the GO lysosomal lumen acidification term is an exact mechanistic match.
- [group] Autophagy-Lysosome Pathway|Lysosomal catabolism|Regulation of lysosomal environment
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a broad PN taxonomy container. The descendants mix components, regulators, context labels, and mechanistic leaves, so propagation should come only from narrower curated nodes.
- [class] Autophagy-Lysosome Pathway|Lysosomal catabolism
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a broad lysosomal-degradation container. The subtree includes carbohydrate, lipid, protein, nuclease, phosphatase, sulfatase, and environment-regulation roles, so mapping should occur at the enzyme or process subtype level.
- [branch] Autophagy-Lysosome Pathway
  status=no_mapping scope= GO=[]
  rationale: Reviewed as the top-level PN branch. It is a project taxonomy umbrella rather than a direct GO assertion; all propagation must come from manually curated child nodes.

Projected GO annotations (3)

GO:0046610 lysosomal proton-transporting V-type ATPase, V0 domain | scope=ok_for_propagation_to_go | goa_status=more_specific_than_existing_goa | from=Autophagy-Lysosome Pathway|Pre-initiation autophagy signaling|mTORC1 pathway, upstream|Nutrient sensing|V0 lysosomal v-ATPase proton pump component
GO:0007042 lysosomal lumen acidification | scope=ok_for_propagation_to_go | goa_status=already_in_goa_exact | from=Autophagy-Lysosome Pathway|Lysosomal catabolism|Regulation of lysosomal environment|Lysosomal acidification
GO:0033179 proton-transporting V-type ATPase, V0 domain | scope=ok_for_propagation_to_go | goa_status=already_in_goa_exact | from=Autophagy-Lysosome Pathway|Lysosomal catabolism|Regulation of lysosomal environment|Lysosomal acidification|V0 lysosomal v-ATPase proton pump component

Note

This file is generated from the current PROTEOSTASIS phase-1 dossier and local gene-review artifacts. Edit the source review, PN mapping, or dossier rather than this generated note when correcting the underlying curation.

📄 View Raw YAML

id: Q93050
gene_symbol: ATP6V0A1
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  ATP6V0A1 encodes the a1 isoform of the V0 membrane sector of the vacuolar H+-ATPase. It is a multi-pass
  membrane subunit that helps assemble the proton-translocation sector of V-ATPase complexes on endolysosomal,
  synaptic vesicle, secretory vesicle, melanosomal, and specialized plasma membranes. By contributing
  to ATP-driven proton transport, ATP6V0A1 supports acidification of lysosomes, endosomes, synaptic vesicles,
  and related organelles; pathogenic variants impair endolysosomal acidification and cause severe neurodevelopmental
  disease with synaptic and autophagy defects.
alternative_products:
  - name: 1 (I)
    id: Q93050-2
  - name: 2 (II)
    id: Q93050-1
    sequence_note: VSP_012814
  - name: '3'
    id: Q93050-3
    sequence_note: VSP_043532, VSP_012814
existing_annotations:
  - term:
      id: GO:0016471
      label: vacuolar proton-transporting V-type ATPase complex
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    qualifier: part_of
    review:
      summary: >-
        Correct core complex annotation. ATP6V0A1 is a subunit of the V0 membrane sector of the vacuolar
        proton-transporting V-type ATPase complex.
      action: ACCEPT
      reason: >-
        The UniProt record and human V-ATPase structure place ATP6V0A1 in the V0 proton-translocation
        sector of the assembled V-ATPase complex.
      additional_reference_ids:
        - file:human/ATP6V0A1/ATP6V0A1-uniprot.txt
        - PMID:33065002
      supported_by:
        - reference_id: file:human/ATP6V0A1/ATP6V0A1-uniprot.txt
          supporting_text: proton transport subunit a, a ring of proteolipid subunits
        - reference_id: PMID:33065002
          supporting_text: Here, we report cryo-EM structures of a human V-ATPase
  - term:
      id: GO:0046961
      label: proton-transporting ATPase activity, rotational mechanism
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    qualifier: contributes_to
    review:
      summary: >-
        Correct as a contributes_to annotation. ATP6V0A1 is not an isolated catalytic ATPase, but as the
        V0 a-subunit it contributes to the rotary proton-pumping activity of the complete V-ATPase.
      action: ACCEPT
      reason: >-
        Human V-ATPase is an ATP-driven proton pump; the a-subunit is part of the membrane proton-translocation
        domain that couples to V1 ATP hydrolysis.
      additional_reference_ids:
        - file:human/ATP6V0A1/ATP6V0A1-uniprot.txt
        - PMID:33065002
        - PMID:34909687
      supported_by:
        - reference_id: PMID:33065002
          supporting_text: ATP hydrolysis-driven proton pumps that acidify intracellular vesicles
        - reference_id: PMID:34909687
          supporting_text: responsible for proton translocation
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    qualifier: is_active_in
    review:
      summary: >-
        Supported but not core for ATP6V0A1. V-ATPases can be present at the plasma membrane in specialized
        contexts, but the main ATP6V0A1 function is organellar acidification.
      action: KEEP_AS_NON_CORE
      reason: >-
        Keep as a specialized-cell localization rather than a core location for the a1 isoform.
      additional_reference_ids:
        - file:human/ATP6V0A1/ATP6V0A1-uniprot.txt
        - PMID:33065002
      supported_by:
        - reference_id: file:human/ATP6V0A1/ATP6V0A1-uniprot.txt
          supporting_text: certain cell types, can be exported to the plasma membrane
  - term:
      id: GO:0007035
      label: vacuolar acidification
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    qualifier: involved_in
    review:
      summary: >-
        Correct core biological process. ATP6V0A1 contributes to V-ATPase-mediated acidification of intracellular
        organelles.
      action: ACCEPT
      reason: >-
        Although lysosomal and endosomal terms are more precise in mammalian cells, vacuolar acidification
        captures the conserved V-ATPase role in organelle lumen acidification.
      additional_reference_ids:
        - file:human/ATP6V0A1/ATP6V0A1-uniprot.txt
        - PMID:33065002
        - PMID:33833240
      supported_by:
        - reference_id: file:human/ATP6V0A1/ATP6V0A1-uniprot.txt
          supporting_text: acidification of various organelles, such as lysosomes, endosomes
        - reference_id: PMID:33833240
          supporting_text: These data suggested that all ATP6V0A1 missense variants impaired
            lysosomal acidification in cell lines.
  - term:
      id: GO:0051117
      label: ATPase binding
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    qualifier: enables
    review:
      summary: >-
        Supported V0-V1 interface annotation, but non-core. ATP6V0A1 binds V1-sector ATPase subunits as
        part of V-ATPase assembly/regulation; this interaction is secondary to the proton-pump function.
      action: KEEP_AS_NON_CORE
      reason: >-
        The ATPase-binding term captures a real subunit-interface property but should not displace the
        complex-level proton transport function as the core molecular role.
      additional_reference_ids:
        - PMID:17360703
        - file:human/ATP6V0A1/ATP6V0A1-uniprot.txt
      supported_by:
        - reference_id: PMID:17360703
          supporting_text: These interactions represent a novel link between the V(1) and V(0)
            domains in man
  - term:
      id: GO:0000220
      label: vacuolar proton-transporting V-type ATPase, V0 domain
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    qualifier: part_of
    review:
      summary: >-
        Correct V0-domain component annotation from InterPro. ATP6V0A1 is the a-subunit of the V0 membrane
        sector.
      action: ACCEPT
      reason: >-
        The V0-domain annotation is central to ATP6V0A1 identity and is supported by UniProt and human
        V-ATPase structural work.
      additional_reference_ids:
        - file:human/ATP6V0A1/ATP6V0A1-uniprot.txt
        - PMID:33065002
      supported_by:
        - reference_id: file:human/ATP6V0A1/ATP6V0A1-uniprot.txt
          supporting_text: proton transport subunit a, a ring of proteolipid subunits
  - term:
      id: GO:0030665
      label: clathrin-coated vesicle membrane
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    qualifier: located_in
    review:
      summary: >-
        Plausible non-core localization. UniProt maps ATP6V0A1 to clathrin-coated vesicle membrane by
        similarity, consistent with V-ATPase function in vesicular compartments.
      action: KEEP_AS_NON_CORE
      reason: >-
        This is a specific vesicle-membrane localization, but the core localization/function is broader
        endolysosomal and synaptic vesicle acidification.
      additional_reference_ids:
        - file:human/ATP6V0A1/ATP6V0A1-uniprot.txt
      supported_by:
        - reference_id: file:human/ATP6V0A1/ATP6V0A1-uniprot.txt
          supporting_text: secretory vesicle, synaptic vesicle
  - term:
      id: GO:0030672
      label: synaptic vesicle membrane
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    qualifier: located_in
    review:
      summary: >-
        Correct neuronal vesicle localization. ATP6V0A1 is annotated to synaptic vesicle membrane, and
        mutant mouse evidence supports a role in synaptic vesicle proton-dependent neurotransmitter loading.
      action: ACCEPT
      reason: >-
        The a1 isoform is brain enriched and supports proton-gradient-dependent synaptic vesicle function.
      additional_reference_ids:
        - file:human/ATP6V0A1/ATP6V0A1-uniprot.txt
        - PMID:33833240
      supported_by:
        - reference_id: file:human/ATP6V0A1/ATP6V0A1-uniprot.txt
          supporting_text: secretory vesicle, synaptic vesicle
        - reference_id: PMID:33833240
          supporting_text: the neurotransmitter content of synaptic vesicles was indeed lowered in
            Atp6v0a1A512P/A512P mice, presumably due to the reduced proton pump activity.
  - term:
      id: GO:0033179
      label: proton-transporting V-type ATPase, V0 domain
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    qualifier: part_of
    review:
      summary: >-
        Correct V0-domain component annotation. This is the generic V0-domain term and is already consistent
        with the PN projection.
      action: ACCEPT
      reason: >-
        ATP6V0A1 is the a-subunit of the V0 proton-translocation sector of V-ATPase.
      additional_reference_ids:
        - file:human/ATP6V0A1/ATP6V0A1-uniprot.txt
        - PMID:33065002
      supported_by:
        - reference_id: file:human/ATP6V0A1/ATP6V0A1-uniprot.txt
          supporting_text: proton transport subunit a, a ring of proteolipid subunits
  - term:
      id: GO:0042470
      label: melanosome
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    qualifier: located_in
    review:
      summary: >-
        Supported but non-core localization. ATP6V0A1 was identified in melanosome fractions, but melanosomes
        are a specialized lysosome-related organelle context rather than the core role of the gene.
      action: KEEP_AS_NON_CORE
      reason: >-
        Retain melanosome localization as a specialized organelle location supported by proteomics and
        UniProt, not as the main ATP6V0A1 function.
      additional_reference_ids:
        - file:human/ATP6V0A1/ATP6V0A1-uniprot.txt
        - PMID:12643545
        - PMID:17081065
      supported_by:
        - reference_id: file:human/ATP6V0A1/ATP6V0A1-uniprot.txt
          supporting_text: melanosome fractions from stage I to stage IV
        - reference_id: PMID:12643545
          supporting_text: identify protein components of early melanosomes
  - term:
      id: GO:0046961
      label: proton-transporting ATPase activity, rotational mechanism
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    qualifier: enables
    review:
      summary: >-
        Correct V-ATPase activity term. ATP6V0A1 contributes to the rotary proton-pumping activity of
        the complete V-ATPase; the term is appropriate when interpreted in the complex-subunit context
        already captured by the IBA contributes_to row.
      action: MODIFY
      reason: >-
        The GO term itself is correct for the V-ATPase complex activity, but the IEA qualifier should be
        changed from enables to contributes_to because ATP6V0A1 is a V0-sector subunit rather than an
        isolated catalytic ATPase.
      proposed_replacement_terms:
        - id: GO:0046961
          label: proton-transporting ATPase activity, rotational mechanism
      additional_reference_ids:
        - file:human/ATP6V0A1/ATP6V0A1-uniprot.txt
        - PMID:33065002
      supported_by:
        - reference_id: PMID:33065002
          supporting_text: ATP hydrolysis-driven proton pumps that acidify intracellular vesicles
  - term:
      id: GO:1902600
      label: proton transmembrane transport
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    qualifier: involved_in
    review:
      summary: >-
        Correct core process. The V0 a-subunit participates directly in proton transmembrane transport
        across organelle membranes.
      action: ACCEPT
      reason: >-
        ATP6V0A1 is part of the membrane proton-translocation domain, and pathogenic variants perturb
        proton translocation/acidification.
      additional_reference_ids:
        - file:human/ATP6V0A1/ATP6V0A1-uniprot.txt
        - PMID:34909687
      supported_by:
        - reference_id: file:human/ATP6V0A1/ATP6V0A1-uniprot.txt
          supporting_text: proton transport subunit a, a ring of proteolipid subunits
        - reference_id: PMID:34909687
          supporting_text: responsible for proton translocation
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:7896830
    qualifier: enables
    review:
      summary: >-
        Remove. The cited publication defines binding of papillomavirus E5 to the 16 kDa V-ATPase proteolipid
        subunit, not ATP6V0A1/a1.
      action: REMOVE
      reason: >-
        This appears to be a mismatched or over-propagated protein-binding annotation. ATP6V0A1 has other
        valid interaction evidence, but PMID:7896830 does not support ATP6V0A1 protein binding.
      additional_reference_ids:
        - PMID:7896830
      supported_by:
        - reference_id: PMID:7896830
          supporting_text: The 16K subunit of the vacuolar H(+)-ATPase binds specifically
  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    qualifier: located_in
    review:
      summary: >-
        Too broad. ATP6V0A1 has cytoplasmic domains but is a multi-pass membrane V-ATPase subunit; cytoplasm
        alone loses the informative membrane/complex localization.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        Prefer membrane-sector and organelle membrane annotations over a broad cytoplasm location.
      additional_reference_ids:
        - file:human/ATP6V0A1/ATP6V0A1-uniprot.txt
      supported_by:
        - reference_id: file:human/ATP6V0A1/ATP6V0A1-uniprot.txt
          supporting_text: Required for assembly and activity of the vacuolar ATPase
  - term:
      id: GO:0048471
      label: perinuclear region of cytoplasm
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    qualifier: located_in
    review:
      summary: >-
        Plausible but non-core transferred localization. Perinuclear cytoplasm is compatible with endolysosomal/Golgi-region
        organelles but is less informative than the specific membrane compartments.
      action: KEEP_AS_NON_CORE
      reason: >-
        Keep as broad cellular context from orthology transfer, while relying on lysosomal/endosomal/synaptic
        vesicle membrane terms for core localization.
      additional_reference_ids:
        - file:human/ATP6V0A1/ATP6V0A1-uniprot.txt
      supported_by:
        - reference_id: file:human/ATP6V0A1/ATP6V0A1-uniprot.txt
          supporting_text: acidification of various organelles, such as lysosomes, endosomes
  - term:
      id: GO:0097401
      label: synaptic vesicle lumen acidification
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    qualifier: involved_in
    review:
      summary: >-
        Correct neuronal process. ATP6V0A1 supports synaptic vesicle proton gradients needed for neurotransmitter
        loading.
      action: ACCEPT
      reason: >-
        Mouse variant data show lowered synaptic vesicle neurotransmitter content, consistent with reduced
        V-ATPase proton-pump activity.
      additional_reference_ids:
        - PMID:33833240
        - file:human/ATP6V0A1/ATP6V0A1-uniprot.txt
      supported_by:
        - reference_id: PMID:33833240
          supporting_text: the neurotransmitter content of synaptic vesicles was indeed lowered in
            Atp6v0a1A512P/A512P mice, presumably due to the reduced proton pump activity.
        - reference_id: file:human/ATP6V0A1/ATP6V0A1-uniprot.txt
          supporting_text: secretory vesicle, synaptic vesicle
  - term:
      id: GO:0007042
      label: lysosomal lumen acidification
    evidence_type: NAS
    original_reference_id: PMID:33065002
    qualifier: involved_in
    review:
      summary: >-
        Correct core lysosomal process. Human ATP6V0A1 variants impair lysosomal acidification, and the
        V-ATPase complex maintains lysosomal pH.
      action: ACCEPT
      reason: >-
        This is one of the strongest ATP6V0A1 process annotations and is directly aligned with the PN
        lysosomal acidification row.
      additional_reference_ids:
        - PMID:33065002
        - PMID:33833240
        - PMID:34909687
      supported_by:
        - reference_id: PMID:33065002
          supporting_text: pH homeostasis of endosomes and lysosomes
        - reference_id: PMID:33833240
          supporting_text: These data suggested that all ATP6V0A1 missense variants impaired
            lysosomal acidification in cell lines.
        - reference_id: PMID:34909687
          supporting_text: direct impairment of endolysosome acidification and failure of lysosomal
            functions.
  - term:
      id: GO:0016020
      label: membrane
    evidence_type: IDA
    original_reference_id: PMID:33065002
    qualifier: located_in
    review:
      summary: >-
        Correct but too broad. ATP6V0A1 is a membrane protein, but generic membrane does not capture its
        V0-sector/endolysosomal and vesicular membrane identity.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        Use specific V-ATPase complex and organelle membrane annotations where possible.
      additional_reference_ids:
        - file:human/ATP6V0A1/ATP6V0A1-uniprot.txt
        - PMID:33065002
      supported_by:
        - reference_id: file:human/ATP6V0A1/ATP6V0A1-uniprot.txt
          supporting_text: Required for assembly and activity of the vacuolar ATPase
  - term:
      id: GO:0033176
      label: proton-transporting V-type ATPase complex
    evidence_type: NAS
    original_reference_id: PMID:33065002
    qualifier: part_of
    review:
      summary: >-
        Correct complex annotation. ATP6V0A1 is part of the proton-transporting V-type ATPase complex
        described structurally in human cells.
      action: ACCEPT
      reason: >-
        The complete human V-ATPase structure and UniProt subunit summary support complex membership.
      additional_reference_ids:
        - file:human/ATP6V0A1/ATP6V0A1-uniprot.txt
        - PMID:33065002
      supported_by:
        - reference_id: PMID:33065002
          supporting_text: Here, we report cryo-EM structures of a human V-ATPase
        - reference_id: file:human/ATP6V0A1/ATP6V0A1-uniprot.txt
          supporting_text: proton transport subunit a, a ring of proteolipid subunits
  - term:
      id: GO:0048388
      label: endosomal lumen acidification
    evidence_type: NAS
    original_reference_id: PMID:32001091
    qualifier: involved_in
    review:
      summary: >-
        Correct process annotation. V-ATPase acidifies endosomes, and ATP6V0A1 contributes to the proton-translocation
        sector.
      action: ACCEPT
      reason: >-
        Endosomal acidification is a core organelle-acidification output of V-ATPase.
      additional_reference_ids:
        - file:human/ATP6V0A1/ATP6V0A1-uniprot.txt
        - PMID:33065002
        - Reactome:R-HSA-74723
      supported_by:
        - reference_id: file:human/ATP6V0A1/ATP6V0A1-uniprot.txt
          supporting_text: acidification of various organelles, such as lysosomes, endosomes
        - reference_id: PMID:33065002
          supporting_text: pH homeostasis of endosomes and lysosomes
        - reference_id: Reactome:R-HSA-74723
          supporting_text: The effect of the proton pump is to allow entry of [H+] ions into the
            lumen of the endosome.
  - term:
      id: GO:1902600
      label: proton transmembrane transport
    evidence_type: NAS
    original_reference_id: PMID:33065002
    qualifier: involved_in
    review:
      summary: >-
        Correct core process. ATP6V0A1 contributes to ATP-driven proton transport across cellular membranes.
      action: ACCEPT
      reason: >-
        This process is supported by V-ATPase structure/function literature and ATP6V0A1 disease variants
        that impair acidification.
      additional_reference_ids:
        - file:human/ATP6V0A1/ATP6V0A1-uniprot.txt
        - PMID:33065002
        - PMID:34909687
      supported_by:
        - reference_id: PMID:33065002
          supporting_text: ATP hydrolysis-driven proton pumps that acidify intracellular vesicles
        - reference_id: PMID:34909687
          supporting_text: responsible for proton translocation
  - term:
      id: GO:0042470
      label: melanosome
    evidence_type: EXP
    original_reference_id: PMID:12643545
    qualifier: located_in
    review:
      summary: >-
        Supported but non-core localization from melanosome proteomics.
      action: KEEP_AS_NON_CORE
      reason: >-
        Melanosome localization is experimentally supported, but it is a specialized lysosome-related
        organelle location rather than the main ATP6V0A1 role.
      additional_reference_ids:
        - file:human/ATP6V0A1/ATP6V0A1-uniprot.txt
        - PMID:12643545
      supported_by:
        - reference_id: file:human/ATP6V0A1/ATP6V0A1-uniprot.txt
          supporting_text: melanosome fractions from stage I to stage IV
        - reference_id: PMID:12643545
          supporting_text: identify protein components of early melanosomes
  - term:
      id: GO:0042470
      label: melanosome
    evidence_type: EXP
    original_reference_id: PMID:17081065
    qualifier: located_in
    review:
      summary: >-
        Supported but non-core localization from melanosome proteomics across developmental stages.
      action: KEEP_AS_NON_CORE
      reason: >-
        Retain as specialized lysosome-related organelle localization; do not treat as the core function.
      additional_reference_ids:
        - file:human/ATP6V0A1/ATP6V0A1-uniprot.txt
        - PMID:17081065
      supported_by:
        - reference_id: file:human/ATP6V0A1/ATP6V0A1-uniprot.txt
          supporting_text: melanosome fractions from stage I to stage IV
        - reference_id: PMID:17081065
          supporting_text: melanosome proteomes at various developmental stages
  - term:
      id: GO:0000220
      label: vacuolar proton-transporting V-type ATPase, V0 domain
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    qualifier: part_of
    review:
      summary: >-
        Correct orthology-supported V0-domain annotation.
      action: ACCEPT
      reason: >-
        The V0-domain role is conserved across V-ATPase a-subunit family members and supported by the
        human UniProt record.
      additional_reference_ids:
        - file:human/ATP6V0A1/ATP6V0A1-uniprot.txt
        - file:interpro/panther/PTHR11629/PTHR11629-metadata.yaml
      supported_by:
        - reference_id: file:human/ATP6V0A1/ATP6V0A1-uniprot.txt
          supporting_text: proton transport subunit a, a ring of proteolipid subunits
        - reference_id: file:interpro/panther/PTHR11629/PTHR11629-metadata.yaml
          supporting_text: VACUOLAR PROTON ATPASES
  - term:
      id: GO:0005765
      label: lysosomal membrane
    evidence_type: TAS
    original_reference_id: PMID:22982048
    qualifier: located_in
    review:
      summary: >-
        Correct lysosomal membrane localization. Although the original TAS citation is indirect, ATP6V0A1
        localization and functional evidence strongly support lysosomal V-ATPase membership.
      action: ACCEPT
      reason: >-
        ATP6V0A1 localizes with lysosomal V-ATPase in cell assays and disease variants impair lysosomal
        acidification.
      additional_reference_ids:
        - file:human/ATP6V0A1/ATP6V0A1-uniprot.txt
        - PMID:33833240
      supported_by:
        - reference_id: PMID:33833240
          supporting_text: These data suggested that all ATP6V0A1 missense variants impaired
            lysosomal acidification in cell lines.
        - reference_id: file:human/ATP6V0A1/ATP6V0A1-uniprot.txt
          supporting_text: acidification of various organelles, such as lysosomes, endosomes
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-6798743
    qualifier: located_in
    review:
      summary: >-
        Supported specialized-cell localization. Reactome places V-ATPase-containing secretory vesicle
        membranes at the plasma membrane during degranulation.
      action: KEEP_AS_NON_CORE
      reason: >-
        This is a contextual trafficking/localization annotation and not the primary ATP6V0A1 function.
      additional_reference_ids:
        - Reactome:R-HSA-6798743
        - file:human/ATP6V0A1/ATP6V0A1-uniprot.txt
      supported_by:
        - reference_id: Reactome:R-HSA-6798743
          supporting_text: Secretory vesicles provide a reservoir of membrane-associated receptors
        - reference_id: file:human/ATP6V0A1/ATP6V0A1-uniprot.txt
          supporting_text: certain cell types, can be exported to the plasma membrane
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-6800426
    qualifier: located_in
    review:
      summary: >-
        Supported specialized neutrophil granule/plasma membrane context, but non-core.
      action: KEEP_AS_NON_CORE
      reason: >-
        Retain as a Reactome-derived specialized localization while keeping organelle acidification as
        the core role.
      additional_reference_ids:
        - Reactome:R-HSA-6800426
        - file:human/ATP6V0A1/ATP6V0A1-uniprot.txt
      supported_by:
        - reference_id: Reactome:R-HSA-6800426
          supporting_text: Ficoli-1 rich granules are a relatively new fourth neutrophil granule
            population
        - reference_id: file:human/ATP6V0A1/ATP6V0A1-uniprot.txt
          supporting_text: certain cell types, can be exported to the plasma membrane
  - term:
      id: GO:0030667
      label: secretory granule membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-6798743
    qualifier: located_in
    review:
      summary: >-
        Supported secretory granule membrane context for V-ATPase-containing vesicles, but non-core.
      action: KEEP_AS_NON_CORE
      reason: >-
        Secretory granules are one organelle class acidified by V-ATPase; this is narrower cellular context
        rather than a separate core function.
      additional_reference_ids:
        - Reactome:R-HSA-6798743
        - file:human/ATP6V0A1/ATP6V0A1-uniprot.txt
      supported_by:
        - reference_id: Reactome:R-HSA-6798743
          supporting_text: Secretory vesicles provide a reservoir of membrane-associated receptors
        - reference_id: file:human/ATP6V0A1/ATP6V0A1-uniprot.txt
          supporting_text: acidification of various organelles, such as lysosomes, endosomes
  - term:
      id: GO:0101003
      label: ficolin-1-rich granule membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-6800426
    qualifier: located_in
    review:
      summary: >-
        Supported ficolin-1-rich granule membrane context in neutrophil degranulation, but non-core.
      action: KEEP_AS_NON_CORE
      reason: >-
        This specific granule class is a specialized immune-cell localization; ATP6V0A1 core function
        remains V-ATPase proton transport.
      additional_reference_ids:
        - Reactome:R-HSA-6800426
        - file:human/ATP6V0A1/ATP6V0A1-uniprot.txt
      supported_by:
        - reference_id: Reactome:R-HSA-6800426
          supporting_text: Ficoli-1 rich granules are a relatively new fourth neutrophil granule
            population
        - reference_id: file:human/ATP6V0A1/ATP6V0A1-uniprot.txt
          supporting_text: acidification of various organelles, such as lysosomes, endosomes
  - term:
      id: GO:0007035
      label: vacuolar acidification
    evidence_type: TAS
    original_reference_id: PMID:22982048
    qualifier: involved_in
    review:
      summary: >-
        Correct organelle acidification process. The original lipofuscin paper is indirect for ATP6V0A1,
        but independent ATP6V0A1 and V-ATPase evidence strongly supports vacuolar/endolysosomal acidification.
      action: ACCEPT
      reason: >-
        Retain the process because it is supported by direct ATP6V0A1 mutant acidification assays and
        general V-ATPase structure/function evidence.
      additional_reference_ids:
        - PMID:33833240
        - PMID:33065002
        - PMID:22982048
      supported_by:
        - reference_id: PMID:33833240
          supporting_text: These data suggested that all ATP6V0A1 missense variants impaired
            lysosomal acidification in cell lines.
        - reference_id: PMID:33065002
          supporting_text: ATP hydrolysis-driven proton pumps that acidify intracellular vesicles
  - term:
      id: GO:0016241
      label: regulation of macroautophagy
    evidence_type: IMP
    original_reference_id: PMID:22982048
    qualifier: involved_in
    review:
      summary: >-
        Keep as non-core. V-ATPase dysfunction causes autophagy defects, but this reflects lysosomal/endolysosomal
        acidification and autophagic flux rather than ATP6V0A1 acting as a dedicated macroautophagy regulator.
      action: KEEP_AS_NON_CORE
      reason: >-
        Aoto and Bott show autophagy defects when ATP6V0A1/V-ATPase function is impaired; the direct core
        function is proton pumping and organelle acidification.
      additional_reference_ids:
        - PMID:33833240
        - PMID:34909687
        - PMID:22982048
        - PMID:28024296
      supported_by:
        - reference_id: PMID:33833240
          supporting_text: Lysosomal dysfunction resulting in cell death, impaired autophagy, and
            reduced mTORC1 signaling and synaptic connectivity
        - reference_id: PMID:22982048
          supporting_text: macroautophagy is responsible for the uptake of lipofuscin into the
            lysosomes.
        - reference_id: PMID:28024296
          supporting_text: localized to the late endosome/lysosome and interacts with the lysosomal
            v-ATPase to negatively regulate mTORC1 activation
  - term:
      id: GO:0070062
      label: extracellular exosome
    evidence_type: HDA
    original_reference_id: PMID:23533145
    qualifier: located_in
    review:
      summary: >-
        High-throughput exosome localization, not a core ATP6V0A1 compartment.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        Exosome proteomics can reflect vesicular trafficking or membrane protein carryover; it does not
        define the main site of ATP6V0A1 function.
      additional_reference_ids:
        - PMID:23533145
      supported_by:
        - reference_id: PMID:23533145
          supporting_text: exosome preparations were characterized by a shotgun proteomics
            procedure.
  - term:
      id: GO:0070062
      label: extracellular exosome
    evidence_type: HDA
    original_reference_id: PMID:19056867
    qualifier: located_in
    review:
      summary: >-
        High-throughput urinary exosome localization, not a core ATP6V0A1 compartment.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        Retain the evidence as a high-throughput detection but do not treat extracellular exosome as a
        primary functional localization.
      additional_reference_ids:
        - PMID:19056867
      supported_by:
        - reference_id: PMID:19056867
          supporting_text: Here, we used LC-MS/MS to profile the proteome of human urinary exosomes.
  - term:
      id: GO:0030670
      label: phagocytic vesicle membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-1222516
    qualifier: located_in
    review:
      summary: >-
        Supported specialized phagocytic vesicle membrane context. V-ATPase acidifies phagosomes, but
        this is a cell-context-specific location.
      action: KEEP_AS_NON_CORE
      reason: >-
        Reactome supports V-ATPase-driven phagosomal acidification; the annotation should remain secondary
        to the general endolysosomal/synaptic vesicle acidification function.
      additional_reference_ids:
        - Reactome:R-HSA-1222516
        - PMID:33065002
      supported_by:
        - reference_id: Reactome:R-HSA-1222516
          supporting_text: ATP hydrolysis drives a 120 degree rotation of the rotor which leads to
            movement of three protons into the phagosome
        - reference_id: PMID:33065002
          supporting_text: ATP hydrolysis-driven proton pumps that acidify intracellular vesicles
  - term:
      id: GO:0010008
      label: endosome membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-5252133
    qualifier: located_in
    review:
      summary: >-
        Correct endosome membrane localization in a V-ATPase assembly/accessory-subunit pathway context.
      action: ACCEPT
      reason: >-
        ATP6V0A1 contributes to V-ATPase complexes on endosomal membranes where proton pumping acidifies
        the endosomal lumen.
      additional_reference_ids:
        - Reactome:R-HSA-5252133
        - file:human/ATP6V0A1/ATP6V0A1-uniprot.txt
        - PMID:33065002
      supported_by:
        - reference_id: PMID:33065002
          supporting_text: pH homeostasis of endosomes and lysosomes
  - term:
      id: GO:0010008
      label: endosome membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-74723
    qualifier: located_in
    review:
      summary: >-
        Correct endosome membrane localization for endosome acidification.
      action: ACCEPT
      reason: >-
        Endosome membrane is a core V-ATPase location and directly matches endosomal acidification evidence.
      additional_reference_ids:
        - Reactome:R-HSA-74723
        - file:human/ATP6V0A1/ATP6V0A1-uniprot.txt
        - PMID:33065002
      supported_by:
        - reference_id: Reactome:R-HSA-74723
          supporting_text: The effect of the proton pump is to allow entry of [H+] ions into the
            lumen of the endosome.
        - reference_id: PMID:33065002
          supporting_text: pH homeostasis of endosomes and lysosomes
  - term:
      id: GO:0010008
      label: endosome membrane
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-917841
    qualifier: located_in
    review:
      summary: >-
        Correct endosome membrane localization in transferrin receptor endosome acidification.
      action: ACCEPT
      reason: >-
        This is a specific Reactome endosomal acidification context for the same core V-ATPase function.
      additional_reference_ids:
        - Reactome:R-HSA-917841
        - file:human/ATP6V0A1/ATP6V0A1-uniprot.txt
        - PMID:33065002
      supported_by:
        - reference_id: Reactome:R-HSA-917841
          supporting_text: Acidification of Tf:TfR1 containing endosome
        - reference_id: PMID:33065002
          supporting_text: pH homeostasis of endosomes and lysosomes
  - term:
      id: GO:0005886
      label: plasma membrane
    evidence_type: IDA
    original_reference_id: PMID:17360703
    qualifier: located_in
    review:
      summary: >-
        Supported but non-core plasma membrane localization. The cited interaction work supports V0-V1
        linkage, while UniProt treats plasma membrane export as cell-type-specific.
      action: KEEP_AS_NON_CORE
      reason: >-
        Use as specialized localization context only; organelle membrane acidification remains the primary
        role.
      additional_reference_ids:
        - PMID:17360703
        - file:human/ATP6V0A1/ATP6V0A1-uniprot.txt
      supported_by:
        - reference_id: PMID:17360703
          supporting_text: These interactions represent a novel link between the V(1) and V(0)
            domains in man
        - reference_id: file:human/ATP6V0A1/ATP6V0A1-uniprot.txt
          supporting_text: certain cell types, can be exported to the plasma membrane
  - term:
      id: GO:0051117
      label: ATPase binding
    evidence_type: IPI
    original_reference_id: PMID:17360703
    qualifier: enables
    supporting_entities:
      - UniProtKB:O75348
    review:
      summary: >-
        Supported V0-V1 interaction with ATP6V1G1/G1, but non-core molecular function.
      action: KEEP_AS_NON_CORE
      reason: >-
        The G-subunit/a-subunit interaction links V1 and V0 domains and is relevant to assembly/regulation,
        but proton transport is the core function.
      additional_reference_ids:
        - PMID:17360703
      supported_by:
        - reference_id: PMID:17360703
          supporting_text: These interactions represent a novel link between the V(1) and V(0)
            domains in man
  - term:
      id: GO:0051117
      label: ATPase binding
    evidence_type: IPI
    original_reference_id: PMID:17360703
    qualifier: enables
    supporting_entities:
      - UniProtKB:Q96LB4
    review:
      summary: >-
        Supported V0-V1 interaction with ATP6V1G3/G3, but non-core molecular function.
      action: KEEP_AS_NON_CORE
      reason: >-
        The G-subunit/a-subunit interaction links V1 and V0 domains and is relevant to assembly/regulation,
        but proton transport is the core function.
      additional_reference_ids:
        - PMID:17360703
      supported_by:
        - reference_id: PMID:17360703
          supporting_text: similar G1/a1, G3/a1, and G1/a4 interactions were also demonstrated
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:12649290
    qualifier: enables
    review:
      summary: >-
        The PFK-1 interaction with the a1 subunit is supported, but generic protein binding is an uninformative
        over-annotation for ATP6V0A1.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        Keep the interaction as context for possible metabolic regulation, but do not treat generic protein
        binding as a core molecular function.
      additional_reference_ids:
        - PMID:12649290
      supported_by:
        - reference_id: PMID:12649290
          supporting_text: An in vitro bead-bound PFK-1 pull-down assay showed that this interaction
            was also true for the ubiquitously expressed a1 subunit.
  - term:
      id: GO:0046610
      label: lysosomal proton-transporting V-type ATPase, V0 domain
    evidence_type: IC
    original_reference_id:
      file:projects/PROTEOSTASIS/reports/pn_projection/pn_projected_candidate_additions.tsv
    qualifier: part_of
    review:
      summary: >-
        NEW annotation from conservative PN projection review. ATP6V0A1 already has generic V0-domain
        and lysosomal membrane/acidification annotations; GO:0046610 adds the lysosomal V0-domain specificity
        supported by the PN row and independent ATP6V0A1/V-ATPase evidence.
      action: NEW
      reason: >-
        The PN candidate is not accepted merely by propagation. It is retained because ATP6V0A1 is a V0-sector
        a-subunit, V-ATPase operates on lysosomal/endolysosomal membranes, and ATP6V0A1 variants directly
        impair lysosomal/endolysosomal acidification.
      additional_reference_ids:
        - file:projects/PROTEOSTASIS/reports/pn_projection/pn_projected_candidate_additions.tsv
        - file:human/ATP6V0A1/ATP6V0A1-uniprot.txt
        - PMID:33833240
        - PMID:34909687
      supported_by:
        - reference_id:
            file:projects/PROTEOSTASIS/reports/pn_projection/pn_projected_candidate_additions.tsv
          supporting_text: "ATP6V0A1\t\tGO:0046610\tlysosomal proton-transporting V-type ATPase, V0 domain"
        - reference_id: file:human/ATP6V0A1/ATP6V0A1-uniprot.txt
          supporting_text: proton transport subunit a, a ring of proteolipid subunits
        - reference_id: PMID:33833240
          supporting_text: These data suggested that all ATP6V0A1 missense variants impaired
            lysosomal acidification in cell lines.
        - reference_id: PMID:34909687
          supporting_text: direct impairment of endolysosome acidification and failure of lysosomal
            functions.
references:
  - id: GO_REF:0000002
    title: Gene Ontology annotation through association of InterPro records with GO terms
    findings: []
  - id: GO_REF:0000024
    title: Manual transfer of experimentally-verified manual GO annotation data to orthologs by
      curator judgment of sequence similarity
    findings: []
  - id: GO_REF:0000033
    title: Annotation inferences using phylogenetic trees
    findings: []
  - id: GO_REF:0000044
    title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary
      mapping, accompanied by conservative changes to GO terms applied by UniProt
    findings: []
  - id: GO_REF:0000107
    title: Automatic transfer of experimentally verified manual GO annotation data to orthologs
      using Ensembl Compara
    findings: []
  - id: PMID:12643545
    title: 'Proteomic analysis of early melanosomes: identification of novel melanosomal proteins.'
    findings: []
  - id: PMID:12649290
    title: The a-subunit of the V-type H+-ATPase interacts with phosphofructokinase-1 in humans.
    findings: []
  - id: PMID:17081065
    title: Proteomic and bioinformatic characterization of the biogenesis and function of
      melanosomes.
    findings: []
  - id: PMID:17360703
    title: V1 and V0 domains of the human H+-ATPase are linked by an interaction between the G and a
      subunits.
    findings: []
  - id: PMID:19056867
    title: Large-scale proteomics and phosphoproteomics of urinary exosomes.
    findings: []
  - id: PMID:22982048
    title: Lipofuscin is formed independently of macroautophagy and lysosomal activity in
      stress-induced prematurely senescent human fibroblasts.
    findings: []
  - id: PMID:23533145
    title: In-depth proteomic analyses of exosomes isolated from expressed prostatic secretions in
      urine.
    findings: []
  - id: PMID:32001091
    title: Structure and Roles of V-type ATPases.
    findings: []
  - id: PMID:33065002
    title: Structures of a Complete Human V-ATPase Reveal Mechanisms of Its Assembly.
    findings:
      - statement: Human V-ATPase structures support ATP6V0A1/V0 complex membership and ATP-driven
          proton-pump function.
  - id: PMID:7896830
    title: Vacuolar H(+)-ATPase mutants transform cells and define a binding site for the
      papillomavirus E5 oncoprotein.
    findings: []
  - id: Reactome:R-HSA-1222516
    title: Intraphagosomal pH is lowered to 5 by V-ATPase
    findings: []
  - id: Reactome:R-HSA-5252133
    title: ATP6AP1 binds V-ATPase
    findings: []
  - id: Reactome:R-HSA-6798743
    title: Exocytosis of secretory granule membrane proteins
    findings: []
  - id: Reactome:R-HSA-6800426
    title: Exocytosis of ficolin-rich granule membrane proteins
    findings: []
  - id: Reactome:R-HSA-74723
    title: Endosome acidification
    findings: []
  - id: Reactome:R-HSA-917841
    title: Acidification of Tf:TfR1 containing endosome
    findings: []
  - id: PMID:33833240
    title: ATP6V0A1 encoding the a1-subunit of the V0 domain of vacuolar H(+)-ATPases is essential
      for brain development in humans and mice.
    findings:
      - statement: ATP6V0A1 disease variants impair lysosomal acidification and synaptic vesicle
          neurotransmitter loading in cell and mouse models.
  - id: PMID:34909687
    title: Variants in ATP6V0A1 cause progressive myoclonus epilepsy and developmental and epileptic
      encephalopathy.
    findings:
      - statement: ATP6V0A1 variants impair endolysosomal acidification and lysosomal function.
  - id: PMID:28024296
    title: mTORC1 and muscle regeneration are regulated by the LINC00961-encoded SPAR polypeptide.
    findings:
      - statement: SPAR localizes to late endosome/lysosome, interacts with lysosomal V-ATPase, and
          negatively regulates amino-acid-stimulated mTORC1 activation.
  - id: file:human/ATP6V0A1/ATP6V0A1-uniprot.txt
    title: UniProt record for ATP6V0A1 (Q93050)
    findings: []
  - id: file:projects/PROTEOSTASIS/reports/pn_projection/pn_projected_candidate_additions.tsv
    title: Proteostasis PN projected candidate additions for ATP6V0A1
    findings:
      - statement: PN projection flags GO:0046610 as more specific than existing ATP6V0A1 GOA
          annotations.
  - id: file:interpro/panther/PTHR11629/PTHR11629-metadata.yaml
    title: PANTHER family PTHR11629 metadata for vacuolar proton ATPases
    findings: []
core_functions:
  - description: >-
      ATP6V0A1 is the a1 subunit of the V0 membrane sector of V-ATPase and contributes to rotary ATP-driven
      proton transport by the assembled complex.
    contributes_to_molecular_function:
      id: GO:0046961
      label: proton-transporting ATPase activity, rotational mechanism
    directly_involved_in:
      - id: GO:1902600
        label: proton transmembrane transport
    in_complex:
      id: GO:0033179
      label: proton-transporting V-type ATPase, V0 domain
    supported_by:
      - reference_id: file:human/ATP6V0A1/ATP6V0A1-uniprot.txt
        supporting_text: proton transport subunit a, a ring of proteolipid subunits
      - reference_id: PMID:33065002
        supporting_text: ATP hydrolysis-driven proton pumps that acidify intracellular vesicles
      - reference_id: PMID:34909687
        supporting_text: responsible for proton translocation
  - description: >-
      As part of V-ATPase complexes on endolysosomal and synaptic vesicle membranes, ATP6V0A1 supports
      acidification of lysosomes, endosomes, and synaptic vesicles, with downstream effects on protein
      degradation, autophagic flux, mTORC1/Notch signaling contexts, and neurotransmitter loading.
    contributes_to_molecular_function:
      id: GO:0046961
      label: proton-transporting ATPase activity, rotational mechanism
    directly_involved_in:
      - id: GO:0007042
        label: lysosomal lumen acidification
      - id: GO:0048388
        label: endosomal lumen acidification
      - id: GO:0097401
        label: synaptic vesicle lumen acidification
      - id: GO:0007035
        label: vacuolar acidification
    locations:
      - id: GO:0005765
        label: lysosomal membrane
      - id: GO:0010008
        label: endosome membrane
      - id: GO:0030672
        label: synaptic vesicle membrane
    in_complex:
      id: GO:0033176
      label: proton-transporting V-type ATPase complex
    supported_by:
      - reference_id: file:human/ATP6V0A1/ATP6V0A1-uniprot.txt
        supporting_text: acidification of various organelles, such as lysosomes, endosomes
      - reference_id: PMID:33065002
        supporting_text: pH homeostasis of endosomes and lysosomes
      - reference_id: PMID:33833240
        supporting_text: These data suggested that all ATP6V0A1 missense variants impaired lysosomal
          acidification in cell lines.
      - reference_id: PMID:33833240
        supporting_text: the neurotransmitter content of synaptic vesicles was indeed lowered in
          Atp6v0a1A512P/A512P mice, presumably due to the reduced proton pump activity.
proposed_new_terms: []
suggested_questions:
  - question: For human ATP6V0A1, which cell types have direct evidence for a1-containing V-ATPase
      at the plasma membrane rather than endolysosomal or secretory vesicle membranes?
  - question: Do the annotated UniProt isoforms differ in compartment targeting or V0 assembly
      efficiency in neurons or other tissues?
suggested_experiments:
  - hypothesis: ATP6V0A1 isoforms differ in endolysosomal versus synaptic vesicle targeting in
      neuronal cells.
    description: Express tagged ATP6V0A1 isoforms at near-endogenous levels in neurons and quantify
      colocalization with lysosomal, endosomal, and synaptic vesicle markers together with
      compartment pH reporters.
    experiment_type: isoform-resolved localization and organelle pH assay

Feature category	ATP6V0A1-specific finding	Key details / evidence	Main sources
Verified identity	Human ATP6V0A1 encodes V-type proton ATPase V0 subunit a1	Matches the neuronal a1 isoform of the V-ATPase V0 sector; corresponds to the largest membrane subunit of the proton-translocating domain (indrawinata2023structuralandfunctional pages 1-2, aoto2021atp6v0a1encodingthe pages 1-2, wang2020structuresofa pages 3-5)	(indrawinata2023structuralandfunctional pages 1-2, aoto2021atp6v0a1encodingthe pages 1-2, wang2020structuresofa pages 3-5)
Complex membership	Core component of the V0 membrane domain of V-ATPase	Human V-ATPase contains V1 ATP-hydrolytic subunits and V0 proton-translocating subunits; Vo includes a1, c-ring subunits, d1, e1, RNaseK, ATP6AP1, ATP6AP2 in the human structure analyzed (wang2020structuresofa pages 3-5)	(wang2020structuresofa pages 3-5)
Domain structure	N-terminal cytosolic domain (aNT) plus C-terminal membrane domain (aCT)	aNT interacts with several V1 and V0 subunits and bridges V1–V0; aCT contains 8 transmembrane helices, with two directly involved in proton transport and formation of the two hemichannels (tuli2023thecytosolicnterminal pages 1-2, tuli2023thecytosolicnterminal pages 2-3)	(tuli2023thecytosolicnterminal pages 1-2, tuli2023thecytosolicnterminal pages 2-3)
Structural role of aNT	Regulatory and assembly hub	The cytosolic aNT contacts V1 E, G, C, and H subunits and acts as part of the stator/collar, helping couple ATP hydrolysis to proton pumping and contributing to isoform-specific regulation/trafficking (tuli2023thecytosolicnterminal pages 1-2, wang2020structuresofa pages 3-5, tuli2023thecytosolicnterminal pages 2-3)	(tuli2023thecytosolicnterminal pages 1-2, wang2020structuresofa pages 3-5, tuli2023thecytosolicnterminal pages 2-3)
Structural role of aCT	Proton pathway-forming membrane domain	aCT contributes the cytoplasmic and luminal hemichannels that allow directional H+ transfer across the membrane during rotary catalysis (tuli2023thecytosolicnterminal pages 1-2, indrawinata2023structuralandfunctional pages 2-4, tuli2023thecytosolicnterminal pages 2-3)	(tuli2023thecytosolicnterminal pages 1-2, indrawinata2023structuralandfunctional pages 2-4, tuli2023thecytosolicnterminal pages 2-3)
Primary biochemical function	ATP-coupled proton translocation into organelle lumen	ATP hydrolysis in V1 drives rotation of the c-ring; ATP6V0A1 provides the proton entry/exit pathway and enables acidification of lysosomes/endosomes and related compartments. The transported substrate is H+ (indrawinata2023structuralandfunctional pages 1-2, wang2020structuresofa pages 1-3, indrawinata2023structuralandfunctional pages 2-4, song2020theemergingroles pages 1-2)	(indrawinata2023structuralandfunctional pages 1-2, wang2020structuresofa pages 1-3, indrawinata2023structuralandfunctional pages 2-4, song2020theemergingroles pages 1-2)
Proton translocation mechanism	Rotary mechanism with c-ring protonation/deprotonation	A proton enters through the cytoplasmic hemichannel, protonates c-ring glutamates, then c-ring rotation brings the protonated site near ATP6V0A1 R740, promoting proton release through the luminal hemichannel and acidifying the lumen; review summarizes ~10 protons translocated per 3 ATP hydrolyzed (indrawinata2023structuralandfunctional pages 2-4)	(indrawinata2023structuralandfunctional pages 2-4)
Critical residue	R740/R741 is the key disease-relevant proton-transfer residue	Homology and disease genetics indicate Arg740/Arg741 is essential for proton transport; human R741Q (also described as R740Q depending on transcript numbering) recurrently causes severe loss of acidification and neurodevelopmental disease (indrawinata2023structuralandfunctional pages 1-2, aoto2021atp6v0a1encodingthe pages 1-2, bott2021variantsinatp6v0a1 pages 1-2, indrawinata2023structuralandfunctional pages 2-4, aoto2021atp6v0a1encodingthe pages 2-4)	(indrawinata2023structuralandfunctional pages 1-2, aoto2021atp6v0a1encodingthe pages 1-2, bott2021variantsinatp6v0a1 pages 1-2, indrawinata2023structuralandfunctional pages 2-4, aoto2021atp6v0a1encodingthe pages 2-4)
Additional channel residues	H748, E794, R804 line the luminal release path	These residues are highlighted in the reviewed proton-release pathway downstream of R740, supporting the luminal hemichannel function of a1 (indrawinata2023structuralandfunctional pages 2-4)	(indrawinata2023structuralandfunctional pages 2-4)
Other disease-linked residues	A512P and N534D impair function without gross mislocalization	Missense variants A512P and N534D reduce lysosomal acidification in stable cell models; these variants lie on the vacuolar/luminal side and are associated with recessive disease when paired with loss-of-function alleles (aoto2021atp6v0a1encodingthe pages 1-2, aoto2021atp6v0a1encodingthe pages 2-4)	(aoto2021atp6v0a1encodingthe pages 1-2, aoto2021atp6v0a1encodingthe pages 2-4)
Tissue expression pattern	Strong neuronal enrichment	ATP6V0A1 is repeatedly described as the brain-enriched / neuronally enriched a-subunit isoform, with major importance for neuronal development, survival, and synaptic function (indrawinata2023structuralandfunctional pages 1-2, aoto2021atp6v0a1encodingthe pages 1-2, falace2024vatpasedysfunctionin pages 1-3, chen2024thedifferentroles pages 2-4)	(indrawinata2023structuralandfunctional pages 1-2, aoto2021atp6v0a1encodingthe pages 1-2, falace2024vatpasedysfunctionin pages 1-3, chen2024thedifferentroles pages 2-4)
Lysosomal localization	Present on lysosomes and required for lysosomal acidification	Wild-type ATP6V0A1 colocalizes with lysosomal marker LAMP2/Lamp2 and V1 subunit ATP6V1A in cell models; pathogenic variants impair lysosomal acidification detected by LysoSensor/LysoTracker assays (aoto2021atp6v0a1encodingthe pages 2-4)	(aoto2021atp6v0a1encodingthe pages 2-4)
Endosomal localization	Prominent localization to endosomes / early and late phagosomes in some cell types	Recent work shows ATP6V0A1 preferentially localizes to endosomes/early-late phagosomes, where it is required for early-to-late endosome/phagosome transition, contrasting with a3/TCIRG1, which is more lysosome-enriched (chen2024thedifferentroles pages 1-2, huang2024atp6v0a1dependentcholesterolabsorption pages 1-2, chen2024thedifferentroles pages 2-4)	(chen2024thedifferentroles pages 1-2, huang2024atp6v0a1dependentcholesterolabsorption pages 1-2, chen2024thedifferentroles pages 2-4)
Synaptic vesicle / presynaptic localization	Delivered to synaptic vesicles and presynaptic membranes	a1 is the neuronal isoform specialized for vesicle acidification needed for neurotransmitter loading; loss of ATP6V0A1 reduces neurotransmitter content of synaptic vesicles in mouse brain (aoto2021atp6v0a1encodingthe pages 1-2, chen2024vatpaseincancer pages 1-3, falace2024vatpasedysfunctionin pages 1-3, chen2024thedifferentroles pages 2-4)	(aoto2021atp6v0a1encodingthe pages 1-2, chen2024vatpaseincancer pages 1-3, falace2024vatpasedysfunctionin pages 1-3, chen2024thedifferentroles pages 2-4)
Autophagy-related localization/function	Functions in autolysosomal pathway rather than as an autophagosome-specific marker	ATP6V0A1-dependent acidification is required for lysosomal degradative capacity and efficient autophagic flux; defects cause accumulation of autophagosomes and lysosomal abnormalities in cells and mouse brain (aoto2021atp6v0a1encodingthe pages 1-2, falace2024vatpasedysfunctionin pages 1-3, song2020theemergingroles pages 1-2)	(aoto2021atp6v0a1encodingthe pages 1-2, falace2024vatpasedysfunctionin pages 1-3, song2020theemergingroles pages 1-2)
Biological processes supported	Endolysosomal degradation, membrane trafficking, neurotransmitter loading, phagosome maturation	ATP6V0A1-dependent acidification supports protein degradation, receptor-mediated endocytosis, small-molecule coupled transport, synaptic vesicle loading, and maturation of phagosomes/endosomes (aoto2021atp6v0a1encodingthe pages 1-2, chen2024thedifferentroles pages 2-4, song2020theemergingroles pages 1-2)	(aoto2021atp6v0a1encodingthe pages 1-2, chen2024thedifferentroles pages 2-4, song2020theemergingroles pages 1-2)
mTORC1 / nutrient signaling link	Supports lysosome-based signaling indirectly through V-ATPase function	V-ATPase is a platform for lysosomal nutrient sensing and mTORC1 regulation; ATP6V0A1 dysfunction in vivo is associated with reduced mTORC1 signaling in brain (aoto2021atp6v0a1encodingthe pages 1-2, falace2024vatpasedysfunctionin pages 1-3, siefert2025mammalianravecouples pages 1-5)	(aoto2021atp6v0a1encodingthe pages 1-2, falace2024vatpasedysfunctionin pages 1-3, siefert2025mammalianravecouples pages 1-5)
Endosome maturation and cholesterol handling	ATP6V0A1 promotes endosome maturation linked to cholesterol uptake	In colorectal cancer cells, ATP6V0A1 facilitates RABGEF1-dependent endosome maturation, enabling exogenous cholesterol absorption and downstream 24-OHC/LXR/TGF-β1 immunosuppressive signaling (huang2024atp6v0a1dependentcholesterolabsorption pages 1-2)	(huang2024atp6v0a1dependentcholesterolabsorption pages 1-2)
Associated V1 partners	Contacts/couples to A, B, C, E, G, H-containing V1 sector	ATP hydrolysis occurs in V1; a1 aNT engages peripheral stalk and collar subunits, helping couple V1 ATPase activity to Vo proton pumping (wang2020structuresofa pages 1-3, wang2020structuresofa pages 3-5, tuli2023thecytosolicnterminal pages 2-3)	(wang2020structuresofa pages 1-3, wang2020structuresofa pages 3-5, tuli2023thecytosolicnterminal pages 2-3)
Associated V0 partners	Works with c-ring, d1, e1, RNaseK, ATP6AP1, ATP6AP2	Human structure places a1 in the Vo complex adjacent to the rotating c-ring and accessory Vo components required for assembly/stability (wang2020structuresofa pages 3-5)	(wang2020structuresofa pages 3-5)
Phenotype of loss/dysfunction	Essential for viability and brain development	Global Atp6v0a1 loss causes embryonic lethality; neuron-specific or pathogenic variant models show neuronal death, defective lysosomal/autophagic function, impaired synaptic connectivity, and epileptic encephalopathy phenotypes (indrawinata2023structuralandfunctional pages 1-2, aoto2021atp6v0a1encodingthe pages 1-2, bott2021variantsinatp6v0a1 pages 1-2)	(indrawinata2023structuralandfunctional pages 1-2, aoto2021atp6v0a1encodingthe pages 1-2, bott2021variantsinatp6v0a1 pages 1-2)

ATP6V0A1

Gene Description

Existing Annotations Review

Core Functions

ATP6V0A1 is the a1 subunit of the V0 membrane sector of V-ATPase and contributes to rotary ATP-driven proton transport by the assembled complex.

As part of V-ATPase complexes on endolysosomal and synaptic vesicle membranes, ATP6V0A1 supports acidification of lysosomes, endosomes, and synaptic vesicles, with downstream effects on protein degradation, autophagic flux, mTORC1/Notch signaling contexts, and neurotransmitter loading.

References

Suggested Questions for Experts

Suggested Experiments

Deep Research

Falcon

Comprehensive Research Report: ATP6V0A1 (V-type Proton ATPase Subunit a1)

Gene Identity Verification

Primary Function and Molecular Mechanism

Enzymatic Activity and Substrate Specificity

Mechanistic Details of Proton Transport

Structural Organization

Subcellular Localization and Tissue Distribution

Organelle-Specific Localization

Tissue Expression Pattern

Biochemical Pathways and Signaling Networks

1. mTORC1 Nutrient Sensing Pathway

2. Autophagy and Protein Quality Control

3. Endocytic Pathway and Membrane Trafficking

4. Cholesterol Metabolism and Immune Regulation

5. pH Homeostasis and Coupled Transport

Biological Processes and Disease Associations

Developmental and Epileptic Encephalopathy (DEE)

Progressive Myoclonus Epilepsy (PME)

Neurodevelopmental Consequences

Alzheimer's Disease and Neurodegeneration

Cancer and Immune Evasion

Experimental Evidence and Model Systems

Mouse Models

Cellular Models

Caenorhabditis elegans

Current Understanding and Recent Developments (2023-2024)

Summary

📚 Additional Documentation

Notes

ATP6V0A1 notes

2026-06-03 - Proteostasis PN review

Falcon deep research synthesis (2026-06-21)

Pn Notes

ATP6V0A1 PN Consistency Notes

Source Files Checked

Deep Research Files

AIGR Review Snapshot

PN Consistency Summary

Full Consistency Review

PN Dossier Context

PN row 1: Autophagy-Lysosome Pathway | Pre-initiation autophagy signaling | mTORC1 pathway, upstream | Nutrient sensing | V0 lysosomal v-ATPase proton pump component

PN row 2: Autophagy-Lysosome Pathway | Lysosomal catabolism | Regulation of lysosomal environment | Lysosomal acidification | V0 lysosomal v-ATPase proton pump component

Projected GO annotations (3)

Note

📄 View Raw YAML